Clinical trial NCT02923193
Conditions: Peripheral Arterial Disease
Sponsor: Shockwave Medical, Inc.
Start date: 2017-02-22; Completion date: 2022-06-02
Enrollment: 306 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Shockwave Medical Inc. intends to conduct a prospective, multi-center, single blind, randomized (1:1) study of Lithoplasty treatment used in combination with DCB versus standard balloon angioplasty used in combination with DCB to treat moderate and severely calcified femoropopliteal arteries. Assuming that roughly 15% of the subjects will be lost-to-follow-up, a total of up to 400 subjects (200 per treatment arm) will be enrolled in the study at up to 60 sites in Europe, the United States and New Zealand.

In addition to the randomized study, an observational study of subjects who do not meet the inclusion/exclusion criteria for the randomized study will be conducted. The objective of the observational study is to assess the real-world acute performance of the Shockwave Medical Peripheral Lithoplasty System in the treatment of calcified, stenotic, peripheral arteries.

The observational study is a prospective, multi-center, single arm observational study for subjects who do not meet the inclusion/exclusion criteria of the randomized study.

A maximum of 1500 subjects at the same 60 sites will be enrolled in the observational study. Once enrollment in the randomized portion of the study is complete, subjects may continue to be enrolled in the observational study provided they meet OS eligibility criteria.

Results for the observational study will be reported in a separate record under NCT05881421.

Detailed description:
Shockwave Medical Inc. intends to conduct a prospective, multi-center, single blind, randomized (1:1) study of Lithoplasty treatment used in combination with DCB versus standard balloon angioplasty used in combination with DCB to treat moderate and severely calcified femoropopliteal arteries. The Shockwave Medical Peripheral Lithoplasty System is indicated for lithotripsy-enhanced, low-pressure balloon dilatation of calcified, stenotic peripheral arteries in patients who are candidates for percutaneous therapy. Up to 400 subjects at 60 sites in Europe, the United States and New Zealand.

Subjects will be followed through discharge, 30 days, and 6, 12 and 24 months. DUS assessments will be completed at 12 and 24 months. Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or stenting by angiographic core lab.

Subjects who do not meet the randomized study inclusion and exclusion criteria, but meet the inclusion and exclusion criteria for the observational study may be enrolled in the observational study. The objective of the observational study is to assess the real-world acute performance of the Shockwave Medical Lithoplasty System in the treatment of calcified, stenotic, peripheral arteries.The observational study is a prospective, multi-center, single arm observational study for subjects who do not meet the inclusion/exclusion criteria of the randomized study. A maximum of 1500 subjects at the same 60 sites will be enrolled in the observational study. Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or stenting by angiographic core lab. Enrollment in the observational study is anticipated to last approximately 22 months. Subjects in the observational study will be followed through hospital discharge. Once enrollment in the randomized portion of the study is complete, subjects may continue to be enrolled in the observational study provided they meet OS eligibility criteria. Results for the observational study will be reported in a separate record under NCT05881421.

Arms: arm 1: Shockwave Lithoplasty® Peripheral Lithoplasty System is a lithotripsy-enhanced, low-pressure balloon dilatation of calcified, stenotic peripheral arteries in patients who are candidates for percutaneous therapy. lithoplasty arm 2: Medronic IN.PACT Drug Coated Balloon (DBS) is indicated for percutaneous transluminal angioplasty (PTA) in patients with obstructive disease of peripheral arteries, including patients with in-stent restenosis (ISR) and arteriovenous (AV) access to help maintain hemodialysis access in patients with end-stage renal disease.
Interventions: intervention 1: Shockwave Lithoplasty® Peripheral Lithoplasty System intervention 2: Medtronic IN.PACT (DCB)
Intervention descriptions: intervention 1: The Shockwave Lithoplasty® System is a proprietary lithotripsy-enhanced balloon catheter that is designed to be delivered through the peripheral arterial system of the lower extremities to the site of calcified stenosis. Activating the lithotripsy within the device will generate pulsatile mechanical energy within the target treatment site, disrupt calcium within the lesion and allow subsequent dilation of a peripheral artery stenosis using low balloon pressure. The system consists of a balloon catheter with multiple integrated lithotripsy electrodes, and a generator. intervention 2: The IN.PACT Admiral DCB is an over-the-wire (OTW) balloon catheter with a drug-coated balloon at the distal tip. The drug component, referred to as the FreePac™ drug coating, consists of the drug paclitaxel and the excipient urea. The device component physically dilates the vessel lumen by PTA, and the drug is intended to reduce the proliferative response that is associated with restenosis.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Prospective Multi-Center, Randomized Post-Market Study (PMS) of the 
Shockwave Medical, Inc. Intravascular Lithotripsy System in Peripheral 
Arteries 
 
NCT02923193 
 
October 10, 2019 


 
NO.:  CP 60892 
REV. F 
TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 1 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
 
 
Randomized study of the Shockwave Medical Peripheral Lithoplasty® System used in 
combination with DCB versus standard balloon angioplasty used in combination with DCB to 
treat moderate and severely calcified femoropopliteal arteries (Disrupt PAD III). 
 
Disrupt PAD III 
 
Protocol Number: CP 60892 
 
Protocol Date: October 10, 2019 
 
Revision: F 
 
Study Devices: Shockwave Medical Peripheral Lithoplasty System and Medtronic IN.PACT DCB 
 
Sponsor Name and Address:  
Shockwave Medical, Inc. 
 
 
 
 
 
5403 Betsy Ross Drive 
 
 
 
 
 
Santa Clara, CA 95054 
 
 
 
 
 
USA 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
THIS STUDY PROTOCOL CONTAINS CONFIDENTIAL INFORMATION FOR USE BY THE INVESTIGATORS AND THEIR 
DESIGNATED REPRESENTATIVES PARTICIPATING IN THE EVALUATION OF THE SHOCKWAVE MEDICAL 
LITHOPLASTY SYSTEM. IT SHOULD BE HELD CONFIDENTIAL AND MAINTAINED IN A SECURE LOCATION.  IT 
SHOULD NOT BE COPIED OR MADE AVAILABLE FOR REVIEW BY ANY UNAUTHORIZED PERSON OR 
FIRM WITHOUT WRITTEN PERMISSION FROM SHOCKWAVE MEDICAL, INC. 


 
NO.:  CP 60892 
REV. F 
TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 2 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
Table of Contents 
1.0 INVESTIGATOR SIGNATURE PAGE ............................................................... 5 
2.0 STUDY SUMMARY............................................................................................ 6 
3.0 INTRODUCTION .............................................................................................. 15 
3.1 Background ........................................................................................................... 15 
3.2 Study Device Description ..................................................................................... 16 
3.2.1 
Shockwave Medical Lithoplasty System ................................................17 
3.2.2 
IN.PACT Admiral DCB..........................................................................18 
3.3 Observational Study Device ................................................................................. 18 
3.4 Indication for Use ................................................................................................. 18 
3.4.1 
Indications for Use outside the United States .........................................18 
3.4.2 
US Indications for Use ............................................................................19 
4.0 STUDY OBJECTIVES ..................................................................................... 20 
4.1 Randomized Study Primary Endpoint .................................................................. 20 
4.2 Randomized Study Secondary Endpoints ............................................................. 20 
4.3 Observational Study Primary Endpoint ................................................................ 21 
5.0 STUDY DESIGN .............................................................................................. 22 
5.1 Study Rationale ..................................................................................................... 22 
5.2 Location ................................................................................................................ 22 
5.3 Number of Subjects............................................................................................... 22 
5.4 Clinical Study Duration ........................................................................................ 23 
6.0 STUDY PROCEDURES ................................................................................... 24 
6.1 Screening............................................................................................................... 24 
6.2 Subject Selection ................................................................................................... 24 
6.2.1 
Randomized Study General Inclusion Criteria .......................................25 
6.2.2 
Randomized Study Angiographic Inclusion Criteria ..............................25 
6.2.3 
Randomized Study General Exclusion Criteria ......................................25 
6.2.4 
Randomized Study Angiographic Exclusion Criteria .............................26 
6.2.5 
Observational Study Inclusion Criteria ...................................................27 
6.2.6 
Observational Study Exclusion Criteria..................................................27 
6.3 Informed Consent.................................................................................................. 27 
6.3.1 
Process for Obtaining Informed Consent ................................................28 
6.3.2 
Subjects Needing Legally Authorized Representative ...........................28 
6.3.3 
Subjects Unable to Read or Write ...........................................................28 
6.3.4 
Addition of New Information .................................................................29 
6.4 Schedule of Events and Evaluations ..................................................................... 29 
6.5 Medications ........................................................................................................... 30 
6.6 Baseline Assessments ........................................................................................... 31 
6.7 Index Procedure .................................................................................................... 32 
6.7.1 
Angiographic Eligibility .........................................................................32 
6.7.2 
Randomized Study Randomization and Enrollment ...............................34 
6.7.3 
Randomized Study Blinding ...................................................................35 


 
NO.:  CP 60892 
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TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 3 OF 77 
 
 
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6.7.4 
Randomized Study Treatment Arm Procedure .......................................36 
6.7.5 
Randomized Study Control Arm Procedure 
6.7.6 
Observational Study Procedure ...............................................................38 
6.8 Follow-Up ............................................................................................................. 39 
6.8.1 
Discharge or Within 12-24 Hours Post Procedure ..................................39 
6.8.2 
30-Day Follow-Up ..................................................................................39 
6.8.3 
6-Month Follow-Up ................................................................................39 
6.8.4 
12-Month Follow-Up ..............................................................................40 
6.8.5 
24-Month Follow-Up ..............................................................................40 
6.8.6 
Prior to target limb revascularization ......................................................40 
6.8.7 
Prospective Health Economic Sub-Study ...............................................41 
6.9 Subject Withdrawal ............................................................................................... 41 
7.0 BENEFITS AND RISKS ................................................................................... 42 
7.1 Benefits ................................................................................................................. 42 
7.2 Risks ...................................................................................................................... 42 
7.3 Mitigation of Risks ............................................................................................... 42 
8.0 STATISTICAL CONSIDERATIONS ................................................................ 43 
8.1 Introduction ........................................................................................................... 43 
8.2 Sample Size Justification ...................................................................................... 43 
8.3 Randomized Study Primary Endpoint – Procedural Success ............................... 44 
8.4 Randomized Study Powered Secondary Effectiveness Endpoint/Primary Patency 45 
8.5 Randomized Study Analysis of Baseline, Secondary Endpoints and Subgroups . 45 
8.6 Randomized Study Secondary Endpoints: ............................................................ 45 
8.7 Randomized Study Analysis Set ........................................................................... 46 
8.7.1 
Primary Analysis Set: .............................................................................46 
8.7.2 
Secondary Analysis Set: .........................................................................46 
9.0 ADVERSE EVENTS......................................................................................... 47 
9.1 Adverse Event Definitions .................................................................................... 47 
9.1.1 
Adverse Event (AE): ...............................................................................47 
9.1.2 
Serious Adverse Event (SAE):................................................................47 
9.1.3 
Adverse Device Effect (ADE): ...............................................................47 
9.1.4 
Serious Adverse Device Effect (SADE): ................................................48 
9.1.5 
Unanticipated Serious Adverse Device Effect (USADE) .......................48 
9.2 Adverse Event Device Relatedness ...................................................................... 48 
9.3 Device Deficiencies .............................................................................................. 49 
9.3.1 
Definitions...............................................................................................49 
9.3.2 
Reporting.................................................................................................49 
9.4 Adverse Event Reporting Requirements ............................................................... 50 
9.4.1 
AE Reporting Requirements ...................................................................50 
9.4.2 
SAE Reporting Requirements .................................................................50 
9.4.3 
ADE Reporting Requirements ................................................................50 
9.4.4 
SADE Reporting Requirements ..............................................................51 


 
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CLASS:  CLINICAL PROTOCOL 
PAGE 4 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
9.4.5 
AE and Device Deficiency Reporting Time Frames ..............................51 
10.0 INVESTIGATOR RESPONSIBILITIES ............................................................ 52 
10.1 EC/IRB Approval.................................................................................................. 52 
10.2 Informed Consent.................................................................................................. 52 
10.3 Protocol Compliance and Delegation of Authority .............................................. 52 
10.4 Medical Care of Subjects ...................................................................................... 52 
10.5 Safety Reporting ................................................................................................... 53 
10.6 Protocol Amendment(s) ........................................................................................ 53 
10.7 Records Retention ................................................................................................. 53 
11.0 SPONSOR RESPONSIBILITIES ..................................................................... 54 
11.1 Selection and Training of Study Sites ................................................................... 54 
11.2 Monitoring of Study Sites ..................................................................................... 54 
11.2.1 
Randomized Study Monitoring Methods ................................................54 
11.2.2 
Randomized Study Monitoring Visits ....................................................55 
11.3 Study Deviations ................................................................................................... 55 
11.4 Device Use Information ........................................................................................ 55 
11.5 Study/Site Suspension or Early Termination ........................................................ 56 
11.6 Study Completion ................................................................................................. 57 
11.7 Audits / Inspections............................................................................................... 57 
11.8 Publication Policies ............................................................................................... 57 
11.9 Data Management ................................................................................................. 57 
11.9.1 
Case Report Forms ..................................................................................57 
11.9.2 
Transmission of Data ..............................................................................58 
11.9.3 
Data Queries............................................................................................58 
11.9.4 
Sponsor Data Retention ..........................................................................58 
12.0 STUDY COMMITTEES .................................................................................... 59 
12.1 Clinical Events Committee (CEC) ........................................................................ 59 
13.0 ETHICAL AND REGULATORY CONSIDERATIONS...................................... 60 
13.1 Role of Shockwave Medical ................................................................................. 60 
13.2 Subject Confidentiality ......................................................................................... 60 
14.0 DEFINITIONS AND LIST OF ABBREVIATIONS ............................................ 61 
14.1 Study Definitions .................................................................................................. 61 
14.2 List of Abbreviations ............................................................................................ 71 
15.0 REVISION HISTORY ....................................................................................... 73 
16.0 BIBLIOGRAPHY .............................................................................................. 76 
 


 
NO.:  CP 60892 
REV. F 
TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 5 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
1.0 
INVESTIGATOR SIGNATURE PAGE 
 
Study Title:  Randomized study of the Shockwave Medical Peripheral Lithoplasty® System 
used in combination with DCB versus standard balloon angioplasty used in 
combination with DCB to treat moderate and severely calcified femoropopliteal 
arteries (Disrupt PAD III). 
 
Study Device: Shockwave Medical Peripheral Lithoplasty System and Medtronic IN.PACT DCB 
 
Protocol Revision: F 
 
Protocol Revision Date: October 10, 2019 
 
Study Sponsor:  
Shockwave Medical, Inc. 
 
 
 
5403 Betsy Ross Drive 
 
 
 
Santa Clara, CA 95054 
 
 
 
USA 
 
 
Principal Investigator Acknowledgement Signature 
 
I have received and reviewed this version of the above noted study protocol and will conduct the 
study in accordance with the investigator requirements. 
 
 
 
____________________________________________             ___________________ 
Investigator’s Name (print)                                                          Site Number 
 
 
 
____________________________________________             ___________________ 
Investigator’s Signature                                                                Date 
 


 
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TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 6 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
2.0 
STUDY SUMMARY 
 
Study Title: 
Randomized study of the Shockwave Medical Peripheral Lithoplasty® 
System used in combination with DCB versus standard balloon 
angioplasty used in combination with DCB to treat moderate and severely 
calcified femoropopliteal arteries (Disrupt PAD III). 
Study Objective:  
The objective of the randomized study is to assess the safety and 
effectiveness of Lithoplasty treatment used in combination with DCB 
versus standard balloon angioplasty used in combination with DCB to treat 
moderate and severely calcified femoropopliteal arteries.   
 
In addition to the randomized study, an observational study (OS) of 
subjects who do not meet the inclusion/exclusion criteria for the 
randomized study will be conducted. The objective of the observational 
study is to assess the real-world acute performance of the Shockwave 
Medical Peripheral Lithoplasty System in the treatment of calcified, 
stenotic, peripheral arteries.  Once enrollment in the randomized portion of 
the study is complete, subjects may continue to be enrolled in the 
observational study provided they meet OS eligibility criteria. 
Study Devices: 
Shockwave Medical Peripheral Lithoplasty System and Medtronic 
IN.PACT DCB. 
Indications for Use:  Indications for Use Outside the United States: 
The Shockwave Medical Peripheral Lithoplasty® System is indicated for 
lithotripsy-enhanced, low-pressure balloon dilatation of calcified, stenotic 
peripheral arteries in patients who are candidates for percutaneous 
therapy. 
 
The IN.PACT Admiral DCB is indicated for percutaneous transluminal 
angioplasty (PTA) in patients with obstructive disease of peripheral 
arteries, including patients with in-stent restenosis (ISR) and arteriovenous 
(AV) access to help maintain hemodialysis access in patients with end-
stage renal disease. 
 
Note: While the IN.PACT Admiral DCB is indicated for use in 
patients with end-stage renal disease who require arteriovenous 
(AV) access to help maintain hemodialysis access, and in patients 
with in-stent restenosis, such patients are not being studied in this 
protocol.   
 
US Indications for Use: 
The Shockwave Medical Lithoplasty System is intended for lithotripsy 


 
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TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 7 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
enhanced balloon dilatation of lesions, including calcified lesions, in the 
peripheral vasculature, including the iliac, femoral, ilio-femoral, popliteal, 
infra-popliteal, and renal arteries. Not for use in the coronary or cerebral 
vasculature. 
 
The IN.PACT Admiral paclitaxel-coated PTA balloon catheter is indicated 
for percutaneous transluminal angioplasty, after appropriate vessel 
preparation, of de novo, restenotic, or in-stent restenotic lesions with 
lengths up to 180 mm in superficial femoral or popliteal arteries with 
reference vessel diameters of 4-7 mm. 
Study Design: 
The Disrupt PAD III is a prospective, multi-center, single blind, randomized 
(1:1) study of Lithoplasty treatment used in combination with DCB versus 
standard balloon angioplasty used in combination with DCB to treat 
moderate and severely calcified femoropopliteal arteries. 
 
The observational study is a prospective, multi-center, single arm 
observational study for subjects who do not meet the inclusion/exclusion 
criteria of the randomized study or for subjects who are recruited after 
enrollment in the randomized portion of the study is complete. 
Enrollment: 
Up to 400 subjects at up to 60 sites in Europe, the United States and New 
Zealand will be enrolled in the randomized study. 
A maximum of 1500 subjects at the same 60 sites will be enrolled in the 
observational study with a minimum of 200 subjects treated with the S4 
Lithoplasty catheter. 
Subject Population: Subjects with moderate and severely calcified femoropopliteal artery 
disease presenting with Rutherford Category 2 to 4 of the target limb in 
the randomized study. 
 
Real-world claudicant or critical limb ischemia (CLI) population in the 
observational study. 
Study Duration / 
Follow-Up Period:  
Approximately 36 months of enrollment for the randomized study at up to 
60 global sites. Randomized study subjects will be followed through 
discharge, 30 days, and 6, 12 and 24 months.  Duplex Ultrasound (DUS) 
assessments will be completed at 12 and 24 months.     
 
Observational study subjects will be followed through hospital discharge. 
Randomized Study 
Primary 
Effectiveness 
Endpoint: 
Procedural success is defined as residual stenosis ≤30% without flow-
limiting dissection (≥ grade D) prior to DCB or stenting by angiographic 
core lab.  
 
Randomized Study 
Powered Secondary 
Primary patency at 12 months defined as freedom from clinically-driven 
target lesion revascularization (TLR) and freedom from restenosis 


 
NO.:  CP 60892 
REV. F 
TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 8 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
Effectiveness 
Endpoint: 
determined by duplex ultrasound or angiogram >50% stenosis.   
As pre-specified, acute PTA failure requiring a stent at any time during the 
index procedure will be counted as a loss of primary patency.   
Randomized Study 
Secondary 
Endpoints: 
 
Major Adverse Event (MAE) at 30 days, 6, 12 and 24 months defined 
as: 
– Need for emergency surgical revascularization of target limb 
– Unplanned target limb major amputation (above the ankle) 
– Symptomatic thrombus or distal emboli that require surgical, 
mechanical or pharmacologic means to improve flow and 
extend hospitalization 
– Perforations that require an intervention, including bail-out 
stenting 
 
Primary patency at 24 months. 
 
Clinically-driven TLR at 30 days, 6, 12 and 24 months. 
 
Ankle-brachial index (ABI) at 30 days, 6, 12 and 24 months reported 
as change from baseline 
 
Rutherford Category at 30 days, 6, 12, and 24 months reported as 
change from baseline. 
 
Quality of Life assessed by EQ-5D questionnaire at 30 days, 6, 12 and 
24 months reported as change from baseline. 
 
Walking capacity assessed by the Walking Impairment Questionnaire 
(WIQ) at 30 days and at 6, 12 and 24 months reported as change from 
baseline 
Randomized Study 
Inclusion Criteria: 
General Inclusion Criteria 
1. Subject is able and willing to comply with all assessments in the 
study. 
2. Subject or subject’s legal representative have been informed of the 
nature of the study, agrees to participate and has signed the 
approved consent form. 
3. Age of subject is > 18.  
4. Rutherford Clinical Category 2, 3, or 4 of the target limb. 
5. Estimated life expectancy >1 year. 
6. Subject is a suitable candidate for angiography and endovascular 
intervention in the opinion of the investigator or per hospital 
guideline.   
7. Subject is intended to undergo treatment with Lithoplasty followed 
by DCB, or DCB with standard balloon pre-dilatation. 
Angiographic Inclusion Criteria 
8. Target lesion that is located in a native, de novo superficial femoral 
artery (SFA) or popliteal artery (popliteal artery extends to and 


 
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REV. F 
TITLE:  DISRUPT PAD III 
CLASS:  CLINICAL PROTOCOL 
PAGE 9 OF 77 
 
 
Confidential – This document is property of Shockwave Medical, Inc. 
ends proximal to the ostium of the anterior tibial artery).   
9. Target lesion reference vessel diameter is between 4.0mm and 
7.0mm by visual estimate. 
10. Target lesion is ≥70% stenosis by investigator via visual estimate.  
11. Target lesion length is ≤180mm for lesions 70-99% stenosed. 
Target lesion can be all or part of the 180mm treated zone. 
12. Chronic total occlusion, lesion length is ≤100mm of the total ≤180 
mm target lesion. 
13. Subject has at least one patent tibial vessel on the target leg with 
runoff to the foot, defined as no stenosis >50%. 
14. Calcification is at least moderate defined as presence of 
fluoroscopic evidence of calcification: 1) on parallel sides of the 
vessel and 2) extending > 50% the length of the lesion if lesion is 
≥50mm in length; or extending for minimum of 20mm if lesion is 
<50mm in length.   
Randomized Study 
Exclusion Criteria: 
General Exclusion Criteria 
1. Rutherford Clinical Category 0, 1, 5 and 6.  
2. Subject has active infection requiring antibiotic therapy. 
3. Planned target limb major amputation (above the ankle). 
4. History of prior endovascular or surgical procedure on the index 
limb within the past 30 days or planned within 30 days of the 
index procedure. 
5. Subject has a known coagulopathy or has bleeding diatheses, 
thrombocytopenia with platelet count less than 100,000/microliter. 
6. Subject in whom antiplatelet or anticoagulant therapy is 
contraindicated. 
7. Subject has known allergy to contrast agents or medications used 
to perform endovascular intervention that cannot be adequately 
pre-treated. 
8. Subject has known allergy to urethane, nylon, or silicone. 
9. Myocardial infarction within 60 days prior to enrollment. 
10. History of stroke within 60 days prior to enrollment. 
11. History of thrombolytic therapy within two weeks of enrollment. 
12. Subject has acute or chronic renal disease defined as serum 
creatinine of >2.5 mg/dL or >220 umol/L, or on dialysis. 
13. Subject is pregnant or nursing.  


 
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14. Subject is participating in another research study involving an 
investigational agent (pharmaceutical, biologic, or medical device) 
that has not reached the primary endpoint.   
15. Subject has other medical, social or psychological problems that, 
in the opinion of the investigator, preclude them from receiving 
this treatment, and the procedures and evaluations pre- and post-
treatment. 
16. The use of specialty balloons, re-entry or atherectomy devices.  
Angiographic Exclusion Criteria 
17.  In-stent restenosis within 10mm of the target zone. 
18. Lesions within 10mm of the ostium of the SFA or within 10mm of 
the ostium of the anterior tibial artery. 
19. Evidence of aneurysm or thrombus in target vessel. 
20. No calcium or mild calcium in the target lesion. 
21. Target lesion within native or synthetic vessel grafts. 
22. Subject has significant stenosis (>50% stenosis) or occlusion of 
inflow tract before target treatment zone (e.g. iliac or common 
femoral) not successfully treated.   
23. Subject requires treatment of a peripheral lesion on the ipsilateral 
limb distal to target site at the time of the index procedure. 
24. Failure to successfully cross the guidewire across the target 
lesion; successful crossing defined as tip of the guidewire distal to 
the target lesion in the absence of flow limiting dissections or 
perforations. 
 
Subjects who do not meet the inclusion/exclusion criteria for the 
randomized study may satisfy the eligibility criteria for the observational 
study.    


 
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CLASS:  CLINICAL PROTOCOL 
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Randomized Study 
Statistical Methods:  
The randomized study is powered to show that the Shockwave Medical 
Peripheral Lithoplasty System is superior to standard balloon angioplasty, 
both in the primary effectiveness endpoint of Procedural Success, and in 
the powered secondary effectiveness endpoint of Primary Patency. 
Procedural Success will be assessed on a per-subject basis. 
The objective of the study is to show that the Procedural Success Rate for 
the Lithoplasty treatment arm is greater than the Procedural Success Rate 
for the PTA treatment arm.  The objective is met when the resulting 
Fisher’s Exact test is statistically significant using a one-sided α = 0.025 
level of statistical significance. 
 
Primary Patency at 12 months will be assessed on a per-subject basis. 
If the primary effectiveness objective is met, then the powered secondary 
effectiveness endpoint will be tested.  The objective of the study is to show 
that the Primary Patency Rate for Lithoplasty followed by DCB treatment 
arm is greater than the Primary Patency Rate for the PTA followed by 
DCB treatment arm.  The objective is met when the resulting Fisher’s 
Exact test is statistically significant using a one-sided α = 0.025 level of 
statistical significance. 
 
The selected baseline variables will be compared between the Lithoplasty 
followed by DCB versus PTA followed by DCB treatment arms. 
Additionally, statistical analyses will be performed for primary and powered 
secondary effectiveness endpoints based on selected subgroups that will 
be defined in the statistical analysis plan. 
 
Primary Analysis Set:  
The primary analysis set will be the Intent-to-Treat (ITT) population.  The 
ITT population includes all randomized subjects, which is the point of 
subject enrollment.    
 
Secondary Analysis Set:  
The secondary analysis set will be the Per-Protocol (PP) population.  The 
PP population includes all subjects who received the correct randomized 
treatment assignment and had no pre-specified inclusion and exclusion 
violation(s).   
 
Observational Study 
Primary 
Effectiveness 
Endpoint: 
Procedural success is defined as final residual stenosis ≤30% without 
flow-limiting dissection (≥ grade D) by angiographic core lab.  
 
Observational Study 
Inclusion Criteria: 
1. Subjects intended to be treated with the Shockwave Medical 
Peripheral Lithoplasty® System for de-novo or restenotic lesions of the 


 
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CLASS:  CLINICAL PROTOCOL 
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Confidential – This document is property of Shockwave Medical, Inc. 
femoral, ilio-femoral, popliteal, and infra-popliteal arteries. 
2. Subjects presenting with claudication or CLI by Rutherford Clinical 
Category 2,3,4,5, or 6 of the target limb. 
3. Age of subject is > 18.  
4. Subject or subject’s legal representative have been informed of the 
nature of the study, agrees to participate, and has signed the approved 
study consent form. 
5. Calcification is at least moderate, defined as presence of fluoroscopic 
evidence of calcification: 1) on parallel sides of the vessel and 2) 
extending > 50% the length of the lesion if lesion is ≥50mm in length; 
or extending for minimum of 20mm if lesion is <50mm in length.   
 
Observational Study 
Exclusion Criteria: 
1. Subjects with any medical condition that would make him/her an 
inappropriate candidate for treatment with Shockwave Medical 
Peripheral Lithoplasty® System as per Instructions for Use (IFU) or 
investigator's opinion. 
2. Subject is already enrolled in other investigational (interventional) 
studies that would interfere with study endpoints. 
Observational Study 
Statistical Methods: 
Descriptive statistics will be reported for the observational study. 
Sponsor 
Study Management: 
Shockwave Medical, Inc. 
Shockwave Medical, Inc. 
5403 Betsy Ross Drive 
Santa Clara, CA 95054 
USA 
 
Contact:  Lahn Fendelander  
Title:  Senior Director, Clinical Affairs 
Telephone: (main): +1 (510) 624-9456 
Telephone (direct): +1 (339) 927-3402 
E-mail: lfendelander@shockwavemedical.com 
Monitoring (CRO), 
Data Management 
and Statistics: 
Clinlogix   
North America Headquarters  
8 Spring House Innovation Park, Suite 100 
Lower Gwynedd, PA 19002 
USA 
 
Contact: Jessica Johnson, MBA 
Title:  Clinical Project Manager 
Telephone: +1 (215) 855-9054 ext. 7025 
E-mail: jessica.johnson@clinlogix.com 


 
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Interactive Web 
Response 
(IWR)/Interactive 
Voice Response 
(IWR): 
Bioclinica, Inc. 
211 Carnegie Center Drive 
Princeton, NJ 08540 USA 
 
Contact: Judy Smith 
Title: Senior Technical Project Manager 
Telephone: +1 (484) 560-5371 
E-mail: judy.smith@bioclinica.com  
Angiographic Core 
Lab: 
Yale Cardiovascular Research Group 
1 Church Street, Suite 330 
New Haven, CT  06510 
USA 
 
Contact: Alexandra J. Lansky, MD 
Title: Director  
Telephone: +1 (203) 737-2142 
Fax: +1 (203) 737-7457 
E-mail: alexandra.lansky@yale.edu 
Clinical Events 
Committee: 
Yale Cardiovascular Research Group 
1 Church Street, Suite 330 
New Haven, CT  06510 
USA 
 
Contact: Louise Gambone, RN, BA 
Title: Director of Operations 
Telephone: +1 (203) 737-2023 
Fax: +1 (203) 737-3427 
E-mail: louise.gambone@yale.edu 
Duplex Ultrasound 
Core Lab: 
Vascular Ultrasound Core Laboratory (VasCore) 
Massachusetts General Hospital 
One Bowdoin Square, 10th Floor, Boston, MA  02114 
USA 
 
Contact : Ido Weinberg, MD 
Telephone: +1 (617) 726-5552 
Fax: +1 (617) 726-1977 
Email: iweinberg@mgh.harvard.edu 


 
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Principal 
Investigators: 
Co-Principal Investigator 
Professor  Dr. Med Gunnar Tepe 
Institut für Diagnostische und Interventionelle Radiologie 
RoMed Klinikum Rosenheim 
83022 Rosenheim  
Germany 
 
Co-Principal Investigator  
William A. Gray, MD 
System Chief of the Division of Cardiovascular Disease 
Main Line Health 
Lankenau Medical Center 
Wynnewood, PA 19096 
USA 
 
 


 
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3.0 
INTRODUCTION 
3.1 Background  
Peripheral arterial disease (PAD) is a chronic occlusive arterial disease caused by 
plaque buildup in the arterial lumen, which leads to diminished blood flow. Disability and 
mortality associated with PAD has increased over the last 20 years and is no longer 
limited to the elderly population and now includes young adults.1  Globally, 202 million 
people were living with PAD in 2010.2  The femoropopliteal artery is the most common 
location for occlusive disease and lower extremity PAD is the third leading cause of 
atherosclerotic cardiovascular morbidity behind cardiovascular disease and stroke.1 
Approximately 15-30% of people with lower extremity PAD will progress from 
intermittent claudication (IC) to critical limb ischemia (CLI)3, 4 and will require some type 
of percutaneous endovascular or surgical procedure to achieve revascularization.   
The presence and extent of calcification adds to the complexity of treating these lesions. 
5, 6  The risk factors most strongly associated with vascular calcification are advanced 
age, diabetes mellitus, chronic kidney disease and hypertension.7 A recent study noted 
those above 70 years of age had vascular calcium present in at least one vascular bed, 
and two-thirds had calcium in all arterial beds. 8 Angiography has been shown to 
underestimate the degree of vascular calcium, which is concerning since it is primarily 
used to determine the appropriate percutaneous strategy for the treatment of PAD. 9 
Calcification increases the risk of vascular complications following treatment with 
angioplasty or stenting including dissections, perforation, distal embolization, TLR and 
binary restenosis. 10, 11, 12, 13, 14    
Traditional interventional therapies for PAD have ongoing complications including acute 
procedure failure and long-term restenosis.  Acute procedural failure is the result of 
incomplete vessel expansion with ongoing high-grade stenosis, or flow-limiting 
dissections, both of which occur in those presenting with greater complexity and degree 
of vascular calcification.   Bail-out stenting with a metallic implant is required in these 
situations to ensure vessel patency.   
Lithoplasty is a balloon-based technology that targets calcification to “normalize” vessel 
compliance prior to low pressure dilatation.  Lithoplasty is designed to optimize acute 
gain while minimizing acute vessel injury and reducing bail-out stenting.  In a recent 
presentation of pooled 30-day results of the DISRUPT PAD program, Lithoplasty 
demonstrated compelling effectiveness and safety results in the treatment of moderately 
and severely calcified vessels with minimal vessel injury, and only one stent implanted 
in 95 subjects.  Acute effectiveness results showed high procedural success across all 
types of lesions and a large acute gain of 3.0mm after the procedure.15 


 
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In the chronic phase, target lesion restenosis leads to recurrence of claudication 
symptoms and may result in repeated revascularizations, sometimes requiring surgical 
bypass to maintain durable patency in the lower extremity.16,17 The advent of biologic 
therapies with anti-proliferative drugs has resulted in a paradigm shift in the treatment of 
PAD.  Drug-coated balloons (DCB) have gained acceptance as a method to deliver 
biologic therapies with the anti-proliferative drug paclitaxel to combat restenosis.  
Recent pivotal studies with DCBs in lesions up to 15-18cm have shown positive 12 
month patency results and a lower need for implants18,19 though they have excluded 
severe calcium.  All-comers DCB studies have enrolled longer lesions without severe 
calcium and have shown an ongoing favorable benefit, though the need for stent 
implantation reaches 40% in longer lesions.20  A recent single-center experience 
suggests severe calcium acts as a barrier to DCBs and results in a dramatic reduction 
in 12 month patency for those with circumferential and long calcium. 21 
Although considerable progress has been made over the last decade, the search 
continues for the optimal treatment strategy in calcified, stenotic PAD that delivers 
durable patency results.  The combination of peripheral Lithoplasty to treat calcification 
and reduce the need for stents, in conjunction with a DCB to reduce restenosis in the 
long term is an attractive therapeutic option for patients with PAD.  The objectives of the 
Disrupt PAD III randomized study are to identify if combination therapy results in 
improved acute gain and less need for stents, as well as an improved long term patency 
when compared to DCB with standard balloon pre-dilatation.  The objective of the 
observational study is to assess the real-world acute performance of the Shockwave 
Medical Peripheral Lithoplasty® in the treatment of calcified, stenotic, peripheral arteries. 
3.2 Study Device Description 
The study devices being evaluated in the randomized study are the Shockwave Medical 
Peripheral Lithoplasty® System (referred to as the Lithoplasty System throughout the 
remainder of this document), and the Medtronic IN.PACT Drug Coated Balloon (DCB).  
The treatment arm of the randomized study will be treated using Lithoplasty and DCB, 
and the control arm will be treated using percutaneous transluminal angioplasty (PTA) 
and DCB. A description of the Lithoplasty System is followed by a description of the 
IN.PACT DCB in the sections below.  
Refer to each manufacturer’s instructions for use (IFU) provided with these 
commercially available devices for a complete product description. 


 
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3.2.1 Shockwave Medical Lithoplasty System 
The Shockwave Medical Lithoplasty System is a proprietary balloon catheter system 
designed to enhance percutaneous transluminal angioplasty by enabling delivery of the 
calcium disrupting capability of lithotripsy prior to balloon dilatation at low pressures. 
The Lithoplasty System consists of a Lithoplasty balloon catheter with five integrated 
pairs of lithotripsy emitters, a Lithoplasty Generator, Connector Cable, and related 
accessories and replacement components. 
The Lithoplasty Catheter is delivered through the peripheral arterial system of the lower 
extremities to the site of an otherwise difficult to treat, calcified stenosis.  The balloon is 
inflated at a lower than nominal pressure and the lithotripsy emitters are energized 
thereby generating pulsatile mechanical energy within the balloon at the target 
treatment site, disrupting calcium within the lesion, and allowing subsequent dilation of a 
peripheral artery stenosis using low balloon pressure.   
 
The balloon is available in 8 sizes:  3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 
6.5 mm, and 7.0 mm diameter and 60 mm length.  The OTW catheter has a working 
length of 110 cm and is compatible with 300 cm length, 0.014” guide wires.  The 
catheter is compatible with 6 or 7Fr introducer sheaths depending on balloon size. The 
catheter tri-lumen hub contains an inflation lumen, a guidewire lumen, and the 
Lithoplasty connector.  The inflation lumen is used for inflation of the balloon with 50/50 
saline/contrast medium.  A Connector Cable is a remote actuator that connects the 
Lithoplasty Generator to the Lithoplasty Catheter and is used to activate energy delivery 
from the Lithoplasty Generator.  
 
The Shockwave S4 Intravascular Lithoplasty Catheter is a line extension and was 
specifically designed to treat calcified below-the-knee (BTK) calcium. Currently, it is 
available for use in the PAD III Observational Study Arm only. 
 
The catheters are available in two sizes of 3.5 mm and 4.0 mm in a 40 mm length and 
are compatible with the Shockwave Lithoplasty generator and connector cable. The 
catheters are 0.014” guidewire and 5F sheath compatible with a 135 cm working 
length.   
 
The Lithoplasty Catheter is supplied sterile via e-beam sterilization.  It is intended for 
single use only and is not intended for reuse or re-sterilization. The Connector Cable 
and Lithoplasty Generator are non-sterile, reusable medical devices.   


 
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3.2.2 IN.PACT Admiral DCB 
The IN.PACT Admiral DCB is an over-the-wire (OTW) balloon catheter with a drug-
coated balloon at the distal tip. The drug component, referred to as the FreePac™ drug 
coating, consists of the drug paclitaxel and the excipient urea. The device component 
physically dilates the vessel lumen by PTA, and the drug is intended to reduce the 
proliferative response that is associated with restenosis.  
PTA Catheter Component 
The IN.PACT Admiral DCB is available in balloon lengths ranging from 20 mm to 120 
mm, balloon diameters ranging from 4.0 mm to 7.0 mm, and in catheter effective 
lengths of 80 cm and 130 cm. The IN.PACT Admiral DCB is compatible with 0.035” 
guidewires. Devices are compatible with 5F (for the 4.0 mm balloon diameter), 6F (for 
the 5.0-6.0 mm balloon diameters), and 7F (for the 7.0 mm balloon diameter) introducer 
sheaths.  
The IN.PACT Admiral DCB is coated with the FreePac™ coating solution, which is a 
proprietary coating with a nominal drug dose density of 3.5 μg of paclitaxel per mm2 of 
the expanded balloon surface. The FreePac™ coating contains a hydrophilic excipient 
(urea) which facilitates the release and transfer of the active pharmaceutical ingredient 
(paclitaxel) into the arterial vessel wall. Additionally, the FreePac™ solution contains 
two solvents, tetrahydrofuran (THF) and pyrogen-free water, which are used during the 
FreePac™ formulation process but evaporate off the balloon surface after the 
FreePac™ coating is applied. 
3.3 Observational Study Device 
Subjects in the observational study will undergo treatment using the Shockwave 
Medical Lithoplasty System. Adjunctive procedures including PTA, DCB or stenting may 
be performed per physician discretion. 
3.4  Indication for Use 
3.4.1 Indications for Use Outside the United States 
The Shockwave Medical Lithoplasty System is indicated for lithotripsy-enhanced, low-
pressure balloon dilatation of calcified, stenotic peripheral arteries in patients who are 
candidates for percutaneous therapy. 
The IN.PACT Admiral is indicated for percutaneous transluminal angioplasty (PTA) in 
patients with obstructive disease of peripheral arteries, including patients with in-stent 
restenosis (ISR) and arteriovenous (AV) access to help maintain hemodialysis access in 
patients with end-stage renal disease. 


 
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Note: While the IN.PACT Admiral DCB is indicated for use in patients with end-stage 
renal disease who require arteriovenous (AV) access to help maintain hemodialysis 
access, and in patients with in-stent restenosis, such patients are not being studied 
in this protocol.   
3.4.2 US Indications for Use 
The Shockwave Medical Lithoplasty System is intended for lithotripsy enhanced balloon 
dilatation of lesions, including calcified lesions, in the peripheral vasculature, including 
the iliac, femoral, ilio-femoral, popliteal, infra-popliteal, and renal arteries.  Not for use in 
the coronary or cerebral vasculature. 
The IN.PACT Admiral paclitaxel-coated PTA balloon catheter is indicated for 
percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo, 
restenotic, or in-stent restenotic lesions with lengths up to 180 mm in superficial femoral 
or popliteal arteries with reference vessel diameters of 4-7 mm. 


 
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4.0 
STUDY OBJECTIVES 
The objective of the randomized study is to assess the safety and effectiveness of 
Lithoplasty treatment used in combination with DCB versus standard balloon 
angioplasty used in combination with DCB to treat moderate and severely calcified 
femoropopliteal arteries.   
Specific objectives will be to assess the impact on: 
1. Procedural success of the vessel treatment prior to DCB or stenting 
2. Provisional stent rate 
3. Primary patency at 12 months 
 
Subjects who do not meet the randomized study inclusion and exclusion criteria, but 
meet the inclusion and exclusion criteria for the observational study may be enrolled in 
the observational study. The objective of the observational study is to assess the real-
world acute performance of the Shockwave Medical Lithoplasty System in the treatment 
of calcified, stenotic, peripheral arteries. 
 
4.1 Randomized Study Primary Endpoint 
Primary Effectiveness Endpoint: 
Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection 
(≥ grade D) prior to DCB or stenting by angiographic core lab.  
 
4.2 Randomized Study Secondary Endpoints 
Powered Secondary Effectiveness Endpoint: 
Primary patency at 12 months defined as freedom from clinically-driven target lesion 
revascularization (TLR) and freedom from restenosis determined by duplex ultrasound 
or angiogram >50% stenosis.  As pre-specified, acute PTA failure requiring a stent at 
any time during the index procedure will be counted as a loss of primary patency.   
Other Secondary Endpoints: 
 
Safety: 
 MAE at 30 days, 6, 12 and 24 months defined as: 
– Need for emergency surgical revascularization of target limb 
– Unplanned target limb major amputation (above the ankle) 
– Symptomatic thrombus or distal emboli that require surgical, mechanical or 
pharmacologic means to improve flow and extend hospitalization 


 
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– Perforations that require an intervention, including bail-out stenting 
 
Patency: 
 Primary patency at 24 months. 
 Clinically-driven TLR at 30 days, 6, 12 and 24 months. 
 
Clinical: 
 
 Ankle-brachial index ABI at 30 days, 6, 12 and 24 months reported as change from 
baseline 
 Rutherford Category at 30 days, 6, 12 and 24 months reported as change from 
baseline. 
 Quality of Life assessed by EQ-5D questionnaire at 30 days, 6, 12 and 24 months 
reported as change from baseline. 
 Walking capacity assessed by the Walking Impairment Questionnaire (WIQ) at 30 
days and at 6, 12 and 24 months reported as change from baseline 
 
4.3 Observational Study Primary Endpoint 
Primary Effectiveness Endpoint: 
Procedural success is defined as final residual stenosis ≤30% without flow-limiting 
dissection (≥ grade D) by angiographic core lab.  


 
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5.0 
STUDY DESIGN 
This protocol includes a prospective, multi-center, single blind, randomized (1:1) study 
of Lithoplasty System treatment used in combination with DCB versus standard balloon 
angioplasty used in combination with DCB to treat moderate and severely calcified 
femoropopliteal arteries. Subjects who do not meet the randomized study  inclusion and 
exclusion criteria, but who meet the observational study inclusion/exclusion criteria may 
be enrolled in that study. The observational study is a prospective, multi-center, single 
arm observational study. 
5.1  Study Rationale  
Both Lithoplasty and the IN.PACT DCB can be used individually, or in combination to 
treat patients with calcified, stenotic femoropopliteal arteries. As noted in the 
introductory section, although considerable progress has been made over the last 
decade, the search continues for the optimal treatment strategy in calcified, stenotic 
PAD that delivers durable patency results.  The combination of peripheral Lithoplasty to 
treat calcification and reduce the need for stents, in conjunction with a DCB to reduce 
restenosis in the long term is an attractive therapeutic option for patients with PAD that 
is available to physicians.  The objectives of the Disrupt PAD III randomized study are to 
identify if this combination therapy results in improved acute gain and less need for 
stents, as well as an improved long-term patency when compared to DCB with standard 
balloon pre-dilatation.   
The objective of the observational study is to assess outcomes of real-world claudicant 
or CLI patients who do not meet the inclusion and exclusion criteria for the randomized 
study, but who are candidates for Lithoplasty System treatment.  
5.2  Location  
Up to sixty (60) global sites will participate in the study. Study sites will be located in 
Europe, the United States, and New Zealand. 
5.3  Number of Subjects 
A maximum of 400 subjects at up to 60 sites with moderate or severely calcified 
femoropopliteal artery disease presenting with Rutherford Category 2 to 4 will be 
enrolled in the randomized study. Each site will be allowed to enroll a maximum of 15% 
(60 subjects) of the total study enrollment.   
 
A maximum of 1500 subjects will be enrolled in the observational study at the same 60 
sites, with a minimum of 200 subjects treated with the S4 Lithoplasty catheter.  


 
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5.4 Clinical Study Duration 
Enrollment in the randomized study is anticipated to last approximately 36 months. 
Subject follow-up intervals are at hospital discharge, at 30 days, and at 6, 12 and 24 
months post-procedure.  DUS assessments will occur at 12 and 24 months.     
Enrollment during the course of the observational study is anticipated to last 
approximately 36 months.  Subjects in the observational study will be followed through 
hospital discharge.  


 
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6.0 
STUDY PROCEDURES 
6.1 Screening  
All patients presenting to the institution with known femoropopliteal disease requiring an 
interventional procedure will be evaluated for eligibility and participation in the 
randomized study. A member of the participating site’s study team will perform an initial 
evaluation of the potential participant’s medical history and previously performed 
examinations to assess for initial eligibility. Pre-procedure imaging (DUS, angiogram, 
CTA, MRA) is recommended, but not mandatory if within institution’s standard-of-care to 
confirm stenosis and calcification ahead of procedural angiography.  
Potential subjects will be screened for eligibility in the randomized study. Written 
informed consent will be obtained prior to any study-specific requirements. A potential 
subject will be informed of the elements of both the randomized and observational 
clinical studies including, risks, potential benefits and required follow-up procedures 
prior to obtaining the potential subject’s informed consent.  No study-specific 
requirements will be performed prior to obtaining informed consent. 
Subjects who meet the inclusion/exclusion criteria for the randomized study will undergo 
an angiogram.  At the time of the angiogram, the subject will be randomized if they meet 
the randomized study angiographic inclusion and exclusion criteria, and a guidewire is 
successfully passed through the target lesion.  A subject is considered an angiographic 
screen failure for the randomized study if they do not meet angiographic eligibility.  
 
If the subject does not meet the inclusion/exclusion criteria for the randomized study or 
presents with calcified stenosis in the iliac, common femoral or below-the-knee, and 
meets the inclusion/exclusion criteria for the observational study, the subject may be 
enrolled in the observational study. Once enrollment in the randomized portion of the 
study is complete, subjects may continue to be enrolled in the observational study 
provided they meet OS eligibility criteria. 
6.2 Subject Selection 
Subjects who meet all general and angiographic inclusion criteria and no general and 
angiographic exclusion criteria of the randomized study will be eligible for enrollment in 
the randomized study. Subjects who do not meet the randomized inclusion and 
exclusion criteria (or subjects recruited after enrollment in the randomized portion of the 
study is complete), but meet inclusion and exclusion criteria of the observational study 
will be eligible for enrollment in the observational study.  
 


 
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6.2.1 Randomized Study General Inclusion Criteria 
1. Subject is able and willing to comply with all assessments in the study. 
2. Subject or subject’s legal representative have been informed of the nature 
of the study, agrees to participate and has signed the approved consent 
form. 
3. Age of subject is > 18.  
4. Rutherford Clinical Category 2, 3, or 4 of the target limb. 
5. Estimated life expectancy >1 year. 
6. Subject is a suitable candidate for angiography and endovascular 
intervention in the opinion of the investigator or per hospital guideline.   
7. Subject is intended to undergo treatment with Lithoplasty followed by DCB 
or DCB with standard balloon pre-dilatation. 
6.2.2 Randomized Study Angiographic Inclusion Criteria 
8. Target lesion that is located in a native, de novo superficial femoral artery 
(SFA) or popliteal artery (popliteal artery extends to and ends proximal to 
the ostium of the anterior tibial artery).   
9. Target lesion reference vessel diameter is between 4.0mm and 7.0mm by 
visual estimate. 
10. Target lesion is ≥70% stenosis by investigator via visual estimate.  
11. Target lesion length is ≤180mm for lesions 70-99% stenosed. Target 
lesion can be all or part of the 180mm treated zone. 
12. Chronic total occlusion, lesion length is ≤100mm of the total ≤180 mm 
target lesion. 
13. Subject has at least one patent tibial vessel on the target leg with runoff to 
the foot, defined as no stenosis >50%. 
14. Calcification is at least moderate defined as presence of fluoroscopic 
evidence of calcification: 1) on parallel sides of the vessel and 2) 
extending > 50% the length of the lesion if lesion is ≥50mm in length; or 
extending for minimum of 20mm if lesion is <50mm in length.   
6.2.3 Randomized Study General Exclusion Criteria 
1. Rutherford Clinical Category 0, 1, 5 and 6.  
2. Subject has active infection requiring antibiotic therapy. 
3. Planned target limb major amputation (above the ankle). 


 
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4. History of prior endovascular or surgical procedure on the index limb 
within the past 30 days or planned within 30 days of the index procedure. 
5. Subject has a known coagulopathy or has bleeding diatheses, 
thrombocytopenia with platelet count less than 100,000/microliter. 
6. Subject in whom antiplatelet or anticoagulant therapy is contraindicated. 
7. Subject has known allergy to contrast agents or medications used to 
perform endovascular intervention that cannot be adequately pre-treated. 
8. Subject has known allergy to urethane, nylon, or silicone. 
9. Myocardial infarction within 60 days prior to enrollment. 
10. History of stroke within 60 days prior to enrollment. 
11. History of thrombolytic therapy within two weeks of enrollment. 
12. Subject has acute or chronic renal disease defined as serum creatinine of 
>2.5 mg/dL or >220 umol/L, or on dialysis.  
13. Subject is pregnant or nursing. 
14. Subject is participating in another research study involving an 
investigational agent (pharmaceutical, biologic, or medical device) that has 
not reached the primary endpoint.   
15. Subject has other medical, social or psychological problems that, in the 
opinion of the investigator, preclude them from receiving this treatment, 
and the procedures and evaluations pre- and post-treatment. 
16. The use of specialty balloons, re-entry or atherectomy devices.  
6.2.4 Randomized Study Angiographic Exclusion Criteria 
17. In-stent restenosis within 10mm of the target zone. 
18. Lesions within 10mm of the ostium of the SFA or within 10mm of the 
ostium of the anterior tibial artery. 
19. Evidence of aneurysm or thrombus in target vessel. 
20. No calcium or mild calcium in the target lesion. 
21. Target lesion within native or synthetic vessel grafts. 
22. Subject has significant stenosis (>50% stenosis) or occlusion of inflow 
tract before target treatment zone (e.g. iliac or common femoral) not 
successfully treated.   
23. Subject requires treatment of a peripheral lesion on the ipsilateral limb 
distal to target site at the time of the index procedure. 


 
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24. Failure to successfully cross the guidewire across the target lesion; 
successful crossing defined as tip of the guidewire distal to the target 
lesion in the absence of flow limiting dissections or perforations. 
6.2.5 Observational Study Inclusion Criteria 
1. Subjects intended to be treated with Shockwave Medical Lithoplasty for 
de-novo or restenotic lesions of the femoral, ilio-femoral, popliteal, and 
infra-popliteal arteries. 
2. Subjects presenting with claudication or CLI by Rutherford Clinical 
Category 2,3,4,5, or 6 of the target limb. 
3. Age of subject is > 18.  
4. Subject or subject’s legal representative have been informed of the nature 
of the study, agrees to participate and has signed the approved consent 
form. 
5. Calcification is at least moderate defined as presence of fluoroscopic 
evidence of calcification: 1) on parallel sides of the vessel and 2) 
extending > 50% the length of the lesion if lesion is ≥50mm in length; or 
extending for minimum of 20mm if lesion is <50mm in length.   
6.2.6 Observational Study Exclusion Criteria 
1. Subjects with any medical condition that would make him/her an 
inappropriate candidate for treatment with Shockwave Lithoplasty as per 
Instructions for Use (IFU) or investigator's opinion. 
2. Subject already enrolled in other investigational (interventional) studies 
that would interfere with study endpoints. 
6.3 Informed Consent 
Prior to undergoing any study specific tests or procedures, the subject (or their legally 
authorized representative) must sign and date the site’s current Ethics Committee (EC) 
or  Institutional Review Board (IRB) and Shockwave Medical approved informed 
consent form in order to be eligible for study participation.  The informed consent must 
contain all elements required by ISO 14155:2011 and be in compliance with the ethical 
principles of the Declaration of Helsinki. 
The potential subject will be informed of the elements of both the randomized and 
observational clinical studies including, risks, potential benefits and required follow-up 
procedures prior to obtaining the potential subject’s informed consent.   
 


 
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6.3.1 Process for Obtaining Informed Consent 
The process for obtaining informed consent is outlined below: 
 The Investigator or his/her authorized designee conducts the informed consent 
process, 
 All aspects of the clinical study that are relevant to the subject's decision to 
participate will be included in the consent form, 
 Investigators will avoid any coercion or undue improper influence on, or 
inducement of, the subject to participate, 
 The consent process shall not waive or appear to waive the subject's legal rights, 
 The consent must use native non-technical language that is understandable to 
the subject, 
 The Investigator, or designee will provide ample time for the subject to read and 
understand the informed consent form and to consider participation in the clinical 
investigation, 
 The consent must include personally dated signatures of the subject and the 
Investigator, or an authorized designee responsible for conducting the informed 
consent process, and/or all signatures required by the reviewing EC/IRB, 
 The Investigator, or designee, will provide the subject with a copy of the signed 
and dated informed consent form and any other written information, 
6.3.2 Subjects Needing Legally Authorized Representative 
Informed consent may be given by a legally authorized representative only if a subject is 
unable to make the decision to participate in a clinical study. In such cases, the subject 
shall also be informed about the clinical study within his/her ability to understand. 
6.3.3 Subjects Unable to Read or Write 
Informed consent shall be obtained through a supervised oral process if a subject or 
legally authorized representative is unable to read or write if allowed by the EC/IRB. An 
independent witness shall be present throughout the process. The written informed 
consent form and any other information shall be explained to the prospective subject or 
his/her legally authorized representative and, whenever possible, either shall sign and 
personally date the informed consent form. The witness also signs and personally dates 
the informed consent form attesting that the information was accurately explained and 
that informed consent was freely given. 


 
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6.3.4 Addition of New Information 
Shockwave Medical will revise the written informed consent form whenever new 
information becomes available that may be relevant to the subject’s confirmed 
participation in the study. The revised information will be sent to the investigator for 
approval by the EC/IRB. After approval by the EC/IRB, a copy of this information must 
be provided to the participating subjects, and the informed consent process as 
described above needs to be repeated.  
6.4 Schedule of Events and Evaluations 
Table 1 lists the schedule of events and evaluations required for the randomized study.  
Table 2 lists the schedule of events and evaluations required for the observational 
study. 
Table 1.  Randomized Study Schedule of Events 
Assessment 
Screening/ 
Baseline1 
Enrollment 
and 
Procedure 
Discharge3 30 Days 
(+/- 7D) 
6 
Months 
(+/- 
30D) 
12 Months 
(+/- 30D) 
24 
Months 
(+/- 30D) 
Pre 
Target 
Limb 
Revasc5 
Informed 
Consent2 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments:  
Chemistry and 
CBC 
X 
 
 
 
 
 
 
 
Urine pregnancy 
test if female1 
X 
 
 
 
 
 
 
 
Walking 
Impairment 
Questionnaire 
X 
 
 
X 
X 
X 
X 
X 
EQ-5D 
X 
 
 
X 
X 
X 
X 
X 
Ankle Brachial 
Index (ABI)1 
X 
 
 
X 
X 
X 
X 
X 
Rutherford 
Category (RC) 
X 
 
 
X 
X 
X 
X 
X 
Angiographic 
Lesion 
Assessment 
 
X 
 
 
 
 
 
X 
Duplex 
Ultrasound 
R4 
 
 
 
 
X 
X 
 


 
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Assessment 
Screening/ 
Baseline1 
Enrollment 
and 
Procedure 
Discharge3 30 Days 
(+/- 7D) 
6 
Months 
(+/- 
30D) 
12 Months 
(+/- 30D) 
24 
Months 
(+/- 30D) 
Pre 
Target 
Limb 
Revasc5 
Medication 
regimen per 
protocol 
X 
 
X 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
1  Evaluations may be done up to 30 days before the procedure with the exception of pregnancy test, which must be 
completed within 7 days of treatment procedure and ABI, which may be completed within 60 days of the procedure. 
2  Consent to be obtained within 30 days prior to treatment procedure. 
3  Examinations are to be completed within 12-24 hours post-procedure or prior to discharge, whichever comes first.  
4 Pre-procedure imaging (DUS, angiogram, CTA, MRA) is recommended, but not mandatory if within Institution’s standard-
of-care to confirm stenosis and calcification ahead of angiography. 
5  Evaluations will be completed prior to a target limb revascularization to assess symptoms and functional status. 
 
 
Table 2.  Observational Study Schedule of Events 
Assessment 
Screening/ 
Baseline1 
Enrollment and 
Procedure 
Discharge3 
 
Informed Consent2 
X 
 
 
Medical History  
X 
 
 
Physical Examination 
 
 
X 
Ankle Brachial Index (ABI)1 
X 
 
 
Rutherford Category (RC) 
X 
 
 
Angiographic Lesion Assessment 
 
X 
 
Duplex Ultrasound 
R4 
 
 
Medication regimen per protocol 
 
 
X 
Adverse Event Assessment 
 
X 
X 
1 Evaluations may be done up to 30 days before the procedure with the exception of ABI, which may be completed within 60 
days of the procedure. 
2 Consent to be obtained within 30 days prior to treatment procedure. 
3  Examinations are to be completed within 12-24 hours post-procedure or prior to discharge, whichever comes first.  
4 Pre-procedure imaging (DUS, angiogram, CTA, MRA) is recommended, but not mandatory if within Institution’s standard-
of-care to confirm stenosis and calcification ahead of angiography. 
 
6.5 Medications 
It is recommended to administer anticoagulation and antiplatelet medications according 
to existing 2011 ESC and 2011 ACC/AHA guidelines for treatment of peripheral arterial 
disease as noted in Table 3 below.    


 
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Table 3.  Anticoagulation / Antiplatelet Medications 
Medication 
Pre-procedure 
During 
Procedure 
Post-procedure 
Aspirin 
 
Loading dose of up to 500 mg 
required, if not on chronic single-
agent antiplatelet therapy. 
N/A 
 
Minimum of 75 
mg/QD for a 
minimum of 30 
days.  
Clopidogrel 
Loading dose of 300-600 mg 
required, if not on chronic single-
agent antiplatelet therapy or 75 mg 
times three days prior to treatment. 
N/A 
 
75 mg/QD for a 
minimum of 30 
days.  
Heparin 
N/A 
Per hospital 
standard of care 
N/A 
Prasugrel*  
Loading dose of 60 mg required, if 
not on chronic single-agent 
antiplatelet therapy or 10 mg times 
three days prior to treatment. 
N/A 
10 mg/QD for 30 
days. 
Ticagrelor*  
Loading dose of 180 mg required, if 
not on chronic antiplatelet therapy. 
 
N/A 
90 mg/BID for a 
minimum of 30 
days. 
* Prasugrel or Ticagrelor as an alternative to clopidogrel is appropriate for existing management of 
acute coronary syndrome (ACS). Follow 2014 ESC myocardial revascularization guidelines: 2014 
ESC/EACTS Guidelines on myocardial revascularization European Heart Journal (2014) 35, 2541–
2619 doi:10.1093/eurheartj/ehu278 
6.6 Baseline Assessments 
Baseline assessments for subjects in the randomized study and the observational study 
must be completed within 30 days of the procedure with the exception of ABI, which can 
be completed within 60 days of the procedure and a pregnancy test, which must be 
done within 7 days of procedure.  Informed consent must be obtained prior to any study-
specific evaluations not considered standard of care needed to assess eligibility.  
Subjects on warfarin or direct thrombin inhibitors should be followed per institutional 
standard of care by the physician.   
Baseline assessments for the randomized study include: 
 Medical history  


 
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 Physical examination 
o Vital signs 
o Height and weight 
o Ankle-brachial index 
o Rutherford Category 
 Laboratory assessments 
 Urine pregnancy test if female of child-bearing age 
 Anticoagulation and antiplatelet medications 
 EQ-5D and WIQ questionnaires 
 
Baseline assessments for the observational study include: 
 Medical History 
 Ankle Brachial Index (ABI) 
 Rutherford Category (RC) 
 
6.7 Index Procedure 
6.7.1 Angiographic Eligibility 
A radiopaque ruler will be placed directly on the subject’s leg under the sterile drapes. 
The end of the ruler is placed at the tibial tubercle. The ruler will serve as a location 
marker for the target lesion being treated the index procedure, and as a reference point 
for follow-up examinations including follow-up duplex evaluations.  
Angiography will be performed per the guidelines established by the core lab, including 
an assessment of the target lesion and distal run-off. All randomized study angiographic 
inclusion and exclusion criteria in Table 4 must be met prior to the decision to 
randomize.  The subject can then be randomized, after a guidewire is successfully 
passed through the target lesion.  The subject is considered an angiographic screen 
failure for enrollment in the randomized study if they do not meet angiographic eligibility. 
The subject may be enrolled in the observational study. 
 
Table 4.  Angiographic Eligibility Assessment 
Inclusion Criteria 
Exclusion Criteria 
Target lesion that is located in a native, 
de novo superficial femoral artery (SFA) 
or popliteal artery (popliteal artery 
extends to and ends proximal to the 
ostium of the anterior tibial artery).   
In-stent restenosis within 10mm of the 
target zone. 
 
Target lesion reference vessel diameter 
Lesions within 10mm of the ostium of the 


 
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Inclusion Criteria 
Exclusion Criteria 
is between 4.0mm and 7.0mm by visual 
estimate. 
SFA or within 10mm of the ostium of the 
anterior tibial artery. 
 
Target lesion is ≥70% stenosis by 
investigator via visual estimate.  
Evidence of aneurysm or thrombus in 
target vessel. 
Target lesion length is ≤180mm for 
lesions 70-99% stenosed. Target lesion 
can be all or part of the 180mm treated 
zone.  
No calcium or mild calcium in the target 
lesion. 
Chronic total occlusion, lesion length is 
≤100mm of the total ≤180 mm target 
lesion. 
Target lesion within native or synthetic 
vessel grafts. 
Subject has at least one patent tibial 
vessel on the target leg with runoff to the 
foot, defined as no stenosis >50%. 
Subject has significant stenosis (>50% 
stenosis) or occlusion of inflow tract 
before target treatment zone (e.g. iliac or 
common femoral) not successfully 
treated.   
Calcification is at least moderate defined 
as presence of fluoroscopic evidence of 
calcification: 1) on parallel sides of the 
vessel and 2) extending > 50% the 
length of the lesion if lesion is ≥50mm in 
length; or extending for minimum of 
20mm if lesion is <50mm in length.   
Subject requires treatment of a 
peripheral lesion on the ipsilateral limb 
distal to target site at the time of the 
index procedure. 
 
 
Failure to successfully cross the 
guidewire across the target lesion; 
successful crossing defined as tip of the 
guidewire distal to the target lesion in the 
absence of flow limiting dissections or 
perforations. 
 
 


 
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6.7.2 Randomized Study Randomization and Enrollment 
The subject will be enrolled in the randomized study after they have signed the study 
informed consent, and all general and angiographic eligibility criteria have been 
confirmed, including successful wire crossing. 
 
Eligible subjects in the randomized study will be randomized in a 1:1 fashion to one of 
the two treatment arms: 
1. Lithoplasty System followed by DCB  or 
2. Standard balloon angioplasty followed by DCB  
 
Randomization will be accomplished using Interactive Voice Response System (IVRS) 
or an online website. Refer to the IVRS randomization instructions on how to randomize 
subjects. Confirmation of randomization assignment will be provided to the site after 
randomization occurs, and must be maintained in the study binders. 
 
Enrollment is defined at the point of randomization.  All randomized subjects will be 
included in the intent to treat analysis.  In the event the subject is not treated or treated 
according to the wrong treatment arm, they will be analyzed according to the treatment 
arm in which they were randomized and followed per protocol.   
 
Figure 1.  Randomized Study flow diagram 


 
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Randomization
Lithoplasty
PTA
Post-dilatation
Post-dilatation
Stent required?
Stent required?
DCB
BMS/DES
DCB
BMS/DES
No
Yes
No
Yes
Assess Procedure 
Success
Assess Procedure 
Success
 
6.7.3 Randomized Study Blinding 
The randomized study is a single blind study.  The randomized study subjects will 
remain blinded through completion of the 12-month follow-up visit for the powered 
secondary effectiveness endpoint. The independent Core Labs and the Clinical Events 
Committee (CEC) will be blinded to the treatment assignment throughout the 24-month 
study duration. 
 
Site staff, including investigators and research coordinators, will not be blinded to 
treatment assignment due to visual differences in the devices in each treatment 
arm.  Shockwave Medical employees and CROs whose responsibilities require 
knowledge of treatment assignment to perform their respective roles will not be blinded. 
These individuals include data management, study  monitors, safety, and regulatory 


 
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staff. Unblinded employees within Shockwave Medical and at the clinical sites will 
receive training to ensure maintenance of the study blinding. 
6.7.4 Randomized Study Treatment Arm Procedure 
Lithoplasty treatment 
A full description of the procedure is detailed in the Instructions for Use (IFU). The 
appropriate sized Lithoplasty balloon catheter should be selected per the IFU.  Once the 
Lithoplasty balloon is placed in the target lesion area, the balloon should be inflated to 4 
ATM and Lithoplasty treatment delivered for the pre-programmed time of 30 seconds to 
deliver 30 pulses.  Note that the generator is programmed to force a minimum pause 
time of 10 seconds following every 30 pulses delivered.  Following the Lithoplasty, 
inflate the balloon to the reference size using the balloon compliance chart (refer to IFU) 
and record lesion response on fluoroscopy.  Deflate the balloon and wait 30 seconds to 
re-establish blood flow.  Repeat the steps above to complete a minimum single 
treatment with 60 pulses.  Additional treatments can be performed if deemed necessary.   
If additional lesion area needs to be treated, follow the treatment steps as identified 
above and per the IFU.  The catheter can be advanced to the next treatment area.  
Confirm the balloon catheter is of the appropriate size for the next treatment area.   
If the operator is unable to pass the Lithoplasty balloon through the lesion, a standard 
PTA balloon, up to 3.0mm, may be used prior to treatment with the Lithoplasty Balloon. 
All efforts should be made to pass the Lithoplasty balloon prior to use of a standard PTA 
balloon.  
Post-dilatation with a semi or non-compliant PTA balloon catheter should be completed 
when post-Lithoplasty results in one of the following below.  The physician should use a 
1:1 balloon catheter to artery ratio and may dilate for up to three minutes.   
 Residual stenosis >30% by visual estimate, or 
 Presence of a flow-limiting (>Grade D) dissection, and 
 
Trans-lesional gradient >10 mm Hg is observed. 
Procedural Success 
Following Lithoplasty and any post-dilatation, an angiographic cine will be obtained to 
assess procedural success of the vessel treatment prior to DCB or stenting.  Follow the 
angiographic core lab procedures to complete angiography showing the target lesion 
with reproducible landmarks for follow-up evaluation and assessment.   
Provisional stenting should be performed with a bare or drug-eluting stent after primary 
treatment or post-dilatation balloon inflations are determined not to be successful.  In 
order to ensure consistency between treatment arms, a provisional stent should be 
placed for an acute PTA failure defined as: 


 
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 Residual stenosis ≥50% by visual estimate, or 
 Un-resolved flow-limiting (>Grade D) dissection, and 
 
Trans-lesional gradient >10 mm Hg is observed. 
The angiographic core lab will confirm correct use of a stent based on the criteria above 
for subjects that receive a provisional stent.  As pre-specified, an acute PTA failure 
requiring a stent at any time during the index procedure will be counted as a loss of 
primary patency.   
DCB (Drug-coated balloon) treatment 
Investigators should follow the Medtronic IN.PACT IFU for instructions on the DCB 
procedure.  No additional pre-dilatation will be required after the Lithoplasty procedure 
and before treatment with a DCB.  Ensure the entire vessel segment dilated with a 
Lithoplasty catheter is covered by a DCB to prevent geographic miss. 
Follow procedures to maximize optimal balloon angioplasty results in the IN.PACT IFU 
including a prolonged inflation of the DCB.   
Final angiogram  
Follow the angiographic core lab procedures to complete final angiography showing the 
target lesion with reproducible landmarks for follow-up evaluation and assessment.  In 
addition, a final distal run-off with imaging to the foot shall be performed to assess for 
procedural complications, including distal embolization and thrombus.   
6.7.5 Randomized Study Control Arm Procedure 
PTA treatment 
PTA treatment can be completed with any commercially available semi or non-
compliant PTA balloon catheters.  No specialty balloons including scoring or cutting 
balloons are permitted.  Investigators should follow the manufacturer’s instructions for 
use to size the reference vessel to the manufacturer’s compliance chart. If additional 
lesion area needs to be treated, follow the treatment steps as identified above and per 
the IFU.  The catheter can be advanced to the next treatment area.  Confirm the balloon 
catheter is of the appropriate size for the next treatment area.   
To ensure consistency between the treatment and control arms, dilatation should be 
done for one minute per treatment area.   
Post-dilatation with a semi or non-compliant PTA balloon catheter should be completed 
when post-PTA results in one of the following below.  The physician should use a 1:1 
balloon catheter to artery ratio and may dilate for up to three minutes.   
 Residual stenosis >30% by visual estimate, or 
 Presence of a flow-limiting (>Grade D) dissection, and 


 
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 
Trans-lesional gradient >10 mm Hg is observed. 
Procedural Success 
Following PTA dilatation and any post-dilatation, an angiographic cine will be obtained 
to assess procedural success of the vessel treatment prior to DCB or stenting.  Follow 
the angiographic core lab procedures to complete angiography showing the target 
lesion with reproducible landmarks for follow-up evaluation and assessment.   
Provisional stenting should be performed with a bare or drug-eluting stent after primary 
treatment or post-dilatation balloon inflations are determined not to be successful.  In 
order to ensure consistency between treatment arms, a provisional stent should be 
placed for an acute PTA failure defined as: 
 Residual stenosis ≥50% by visual estimate, or 
 Un-resolved flow-limiting (>Grade D) dissection, and 
 
Trans-lesional gradient >10 mm Hg is observed. 
The angiographic core lab will confirm correct use of a stent based on the criteria above 
for subjects that receive a provisional stent.  As pre-specified, an acute PTA failure 
requiring a stent will be counted as a loss of primary patency.   
Drug-coated balloon treatment 
Investigators should follow the Medtronic IN.PACT IFU for instructions on the DCB 
procedure.  Ensure the entire vessel segment dilated with PTA balloon catheter is 
covered by a DCB to prevent geographic miss. 
Follow procedures to maximize optimal balloon angioplasty results in the IN.PACT IFU 
including a prolonged inflation of the DCB.   
Final angiogram 
Follow the angiographic core lab procedures to complete a final angiographic cine 
showing the target lesion with reproducible landmarks for follow-up evaluation and 
assessment.  In addition, a final distal run-off with imaging to the foot shall be performed 
to assess for procedural complications, including distal embolization and thrombus.   
6.7.6 Observational Study Procedure 
For subjects enrolled in the observational study, Lithoplasty treatment should be 
administered as indicated in section 6.7.4 and in accordance with the procedure details 
in the IFU.  Adjunctive procedures including PTA, DCB or stenting may be performed 
per physician discretion.  
Procedural success and final angiogram  
Angiographic cines will be obtained to assess procedural success of the vessel 
treatment post-Lithoplasty and following any adjunctive procedures, if performed.  In 


 
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addition, a final distal run-off with imaging to the foot shall be performed to assess for 
procedural complications, including distal embolization and thrombus.   
6.8 Follow-Up 
6.8.1 Discharge or Within 12-24 Hours Post Procedure 
The following assessments and procedures will be performed within 12-24 hours post 
procedure or prior to hospital discharge, whichever occurs first for subjects in the 
randomized and observational study: 
 Follow up visit assessments including: 
o Physical examination  
o Target review of symptoms  
 Adverse event assessment 
 Anticoagulation and antiplatelet medications 
 
6.8.2 
30-Day Follow-Up  
The following evaluations will be scheduled for 30 days (+/-7 days) post procedure for 
subjects in the randomized study only: 
 Follow-up visit assessments including: 
o Physical examination 
o Rutherford Category 
o ABI (at rest or after exercise; keep consistent with screening) 
o Target review of symptoms 
 EQ-5D and WIQ questionnaires 
 Adverse event assessment 
 Anticoagulation and antiplatelet medications 
 
6.8.3 
6-Month Follow-Up  
The following evaluations will be scheduled for 6 months [180 days (+/-30 days)] post 
procedure for subjects in the randomized study only: 
 Follow-up visit assessments including: 
o Physical Examination 
o Rutherford Category 
o ABI (at rest or after exercise; keep consistent with screening) 
o Target review of symptoms 
 EQ-5D and WIQ questionnaires 
 Adverse event assessment 
 Anticoagulation and antiplatelet medications 
 


 
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6.8.4 
12-Month Follow-Up  
The following evaluations will be scheduled for 12 months [365 days (+/- 30 days)] post 
procedure for subjects in the randomized study only: 
 Follow-up visit assessments including: 
o Physical Examination 
o Rutherford Category 
o ABI (at rest or after exercise; keep consistent with screening) 
o Target review of symptoms 
 EQ-5D and WIQ questionnaires 
 Duplex ultrasound 
 Adverse event assessment 
 Anticoagulation and antiplatelet medications 
 
6.8.5 
24-Month Follow-Up  
The following evaluations will be scheduled for 24 months [730 days (+/- 30 days)] post 
procedure for subjects in the randomized study only: 
 Follow-up visit assessments including: 
o Physical Examination 
o Rutherford Category 
o ABI (at rest or after exercise; keep consistent with screening) 
o Target review of symptoms 
 EQ-5D and WIQ questionnaires 
 Duplex ultrasound 
 Adverse event assessment 
 Anticoagulation and antiplatelet medications 
 
6.8.6 
Prior to target limb revascularization 
The following evaluations will be completed prior to any target limb revascularization to 
assess symptoms and functional status prior to revascularization.   
 
o Physical Examination 
o Rutherford Category 
o ABI (at rest or after exercise; keep consistent with screening) 
o Target review of symptoms 
 EQ-5D and WIQ questionnaires 
 Angiographic Lesion Assessment 
 


 
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6.8.7 
Prospective Health Economic Sub-Study  
A prospective health economic sub-study will be conducted at the US study sites for 
both the Randomized and the Observational study. For the Randomized study costs for 
the index procedure and costs related to PAD treatment of the target limb will be 
collected through 24 months of follow-up for both treatment arms.  Subjects enrolled in 
the Observational study will have the cost of their index procedure collected. The 
objective is to understand the cost effectiveness of these two approaches on peripheral 
artery revascularization.   
6.9 Subject Withdrawal 
A study subject has the right to discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled. A subject that has withdrawn 
from the study will be treated according to standard of medical care and will not be 
replaced.  
 


 
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7.0 
BENEFITS AND RISKS 
7.1 Benefits 
There are no guaranteed benefits from participation in the study. The randomized study 
will provide safety and effectiveness data of Lithoplasty treatment used in combination 
with DCB versus DCB with standard balloon pre-dilatation to treat moderate and 
severely calcified femoropopliteal arteries. The observational study will provide 
outcomes data for the real-world claudicant or CLI populations. These clinical results 
may inform physicians in determining the optimal treatment strategy for this patient 
population.  
7.2 Risks 
For detailed information on the risks of the devices used in the study procedure, 
including a complete list of warnings, precautions and potential adverse events, please 
refer to the Instructions for Use for the Lithoplasty System and the IN.PACT DCB 
provided with the products. It is important to ensure that the IFU referred to represents 
the generation of both of the devices used in the study procedure. 
7.3 Mitigation of Risks  
As with any endovascular procedure, appropriate safety precautions will be followed.  
Risks of observed or theoretical adverse events have been mitigated through the 
Instructions for Use, physician training, and patient selection in the study protocol. 
All efforts will be made to minimize these risks by:  
 Site selection  
 Ensuring compliance to the protocol and IFU 
 Study Monitoring 
 Safety processes – protocol adverse event reporting requirements, CEC 
oversight, and safety reporting to regulatory authorities including Vigilance 
reporting/US Medical Device Reporting, if required 
 Risk management process 


 
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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Introduction 
The randomized study is a prospective, multi-center, single blind, randomized (1:1) 
study of Lithoplasty treatment used in combination with DCB versus standard balloon 
angioplasty used in combination with DCB to treat moderate and severely calcified 
femoropopliteal arteries.  
A maximum of 400 subjects will be enrolled at up to 60 sites located in Europe, the 
United States and New Zealand. 
The objective of the study is to assess the safety and effectiveness of Lithoplasty 
treatment used in combination with DCB versus standard balloon angioplasty used in 
combination with DCB to treat moderate and severely calcified femoropopliteal arteries.   
Specific objectives will be to assess the impact on: 
1. Procedural success of the vessel treatment prior to DCB or stenting 
2. Provisional stent rate 
3. Primary patency at 12 months 
The observational study will assess baseline, procedural, and hospital discharge 
outcomes of Lithoplasty used in the treatment of subjects with calcified, stenotic, 
peripheral arteries. 
8.2 
Sample Size Justification 
The randomized study is powered to show that the Shockwave Medical Peripheral 
Lithoplasty System is superior to standard balloon angioplasty, both in the primary 
effectiveness endpoint of Procedural Success, and in the powered secondary 
effectiveness endpoint of Primary Patency. 
For the primary effectiveness endpoint of Procedural Success, assume the following: 
Statistical Hypothesis: 
H0: 
πTreatment 
< 
πControl 
vs 
H1: 
πTreatment 
> 
πControl, 
where πTreatment is the Procedural Success Rate for the 
Lithoplasty Treatment arm, and πControl is the Procedural 
Success Rate for the PTA Treatment arm. 
Statistical Test: 
 
Fisher’s Exact test  
Statistical Significance: 
one-sided α = 0.025  
Statistical Power: 
 
1 – β = 0.80 
Expected Success Rates: πTreatment = 0.85 and πControl = 0.62 


 
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Minimum Sample Size: 
n =  130 subjects, 65 per treatment arm 
 
For the powered secondary effectiveness endpoint of Primary Patency at 12-Months, 
assume the following: 
Statistical Hypothesis: 
H0: 
πTreatment 
< 
πControl 
vs 
H1: 
πTreatment 
> 
πControl, 
where πTreatment is the Primary Patency Rate for the 
Lithoplasty followed by DCB  Treatment arm, and πControl is 
the Primary Patency Rate for the PTA followed by DCB 
Treatment arm. 
Statistical Test: 
 
Fisher’s Exact test  
Statistical Significance: 
one-sided α = 0.025  
Statistical Power: 
 
1 – β = 0.85 
Expected Success Rates: πTreatment = 0.78 and πControl = 0.61 
Minimum Sample Size: 
n = 284 subjects, 142 per treatment arm 
The sample size requirements for the powered secondary effectiveness endpoint 
exceed those for the primary effectiveness endpoint.  As a result, the powered 
secondary effectiveness endpoint will be used to calculate the minimum required 
sample size for the study.  Assuming that roughly 15% of the subjects will be lost-to-
follow-up, a total of 334 subjects (167 per treatment arm) is required for the powered 
secondary endpoint. In total, up to 400 subjects may be enrolled. 
The observational study will include a maximum of 1500 subjects. Data collection for 
these subjects will include evaluations at baseline, procedural and hospital discharge 
intervals only.  
 
8.3 
Randomized Study Primary Endpoint – Procedural Success 
Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection 
(≥ grade D) prior to DCB or stenting by angiographic core lab.  
Procedural Success will be assessed on a per-subject basis. 
The objective of the study is to show that the Procedural Success Rate for the 
Lithoplasty treatment arm is greater than the Procedural Success Rate for the PTA 
treatment arm.  The objective is met when the resulting Fisher’s Exact test is statistically 
significant using a one-sided α = 0.025 level of statistical significance. 
 


 
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8.4 
Randomized Study Powered Secondary Effectiveness Endpoint 
– Primary Patency 
The powered secondary effectiveness endpoint for the randomized study is Primary 
Patency at 12 months defined as freedom from clinically-driven target lesion 
revascularization (TLR) and freedom from restenosis determined by duplex ultrasound 
or angiogram >50% stenosis.   
Primary Patency will be assessed on a per-subject basis. 
If the primary effectiveness objective is met, then the powered  secondary effectiveness 
endpoint will be tested.  The objective of the study is to show that the Primary Patency 
Rate for the Lithoplasty followed by DCB treatment arm is greater than the Primary 
Patency Rate for the PTA followed by DCB treatment arm.  The objective is met when 
the resulting Fisher’s Exact test is statistically significant using a one-sided α = 0.025 
level of statistical significance. 
 
8.5 
Randomized Study Analysis of Baseline, Secondary Endpoints 
and Subgroups 
Baseline variables will be compared between the Lithoplasty followed by DCB versus 
DCB with standard balloon pre-dilatation treatment arms. 
 
Descriptive statistics for the secondary endpoints will be provided.  Analyses will be 
provided at pre-specified time points including 30 day, 6, 12 or 24 months.  In the event 
of a target limb or vessel revascularization, the data immediately prior to the 
revascularization will be applied for Rutherford Category, ABI, WIQ and EQ-5D 
secondary endpoints. 
 
Additionally, statistical analyses will be performed for primary and powered secondary 
effectiveness endpoints based on selected subgroups that will be defined in the 
statistical analysis plan. 
 
8.6 
Randomized Study Secondary Endpoints: 
Other randomized study secondary endpoints include the following: 
 
Safety: 
 MAE at 30 days, 6, 12 and 24 months defined as: 
– Need for emergency surgical revascularization of target limb 
– Unplanned target limb major amputation (above the ankle) 
– Symptomatic thrombus or distal emboli that require surgical, mechanical or 
pharmacologic means to improve flow and extend hospitalization 


 
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– Perforations that require an intervention, including bail-out stenting 
 
Patency: 
 Primary patency at 12 months. 
 Clinically-driven TLR at 30 days, 6, 12 and 24 months. 
 
Clinical: 
 
 Ankle-brachial index ABI at 30 days, 6, 12 and 24 months reported as change from 
baseline 
 Rutherford Category at 30 days, 6, 12 and 24 months reported as change from 
baseline. 
 Quality of Life assessed by EQ-5D questionnaire at 30 days, 6, 12 and 24 months 
reported as change from baseline. 
 Walking capacity assessed by the Walking Impairment Questionnaire (WIQ) at 30 
days and at 6, 12 and 24 months reported as change from baseline 
 
8.7 
Randomized Study Analysis Set 
8.7.1 
Primary Analysis Set:  
The primary analysis set for the randomized study will be the Intent-to-Treat (ITT) 
population.  The ITT population includes all randomized subjects, which is the point of 
subject enrollment.    
 
8.7.2 
Secondary Analysis Set:  
The secondary analysis set for the randomized study will be the Per-Protocol (PP) 
population.  The PP population includes all subjects who received the correct 
randomized treatment assignment and had no pre-specified inclusion and exclusion 
violation(s).   


 
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9.0 
ADVERSE EVENTS 
Standard definitions and reporting requirements for reportable adverse events for the 
randomized and observational study are provided below. 
9.1  Adverse Event Definitions 
9.1.1 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 study medical device.  
This definition includes events related to the investigational medical device or the 
comparator.  This definition includes events related to the procedures involved. 
9.1.2 Serious Adverse Event (SAE):  
An adverse event that  
a) led to death 
b) led to a serious deterioration in the health of a subject that either resulted in  
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient or prolonged hospitalization, or  
4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to body structure or a body function 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect.   
Planned hospitalization for a pre-existing condition, or a procedure required by the study 
protocol without serious deterioration in health, is not considered a serious adverse 
event. 
9.1.3 Adverse Device Effect (ADE):   
An adverse device effect is defined as any untoward adverse event related to the use of 
an investigational or study medical device.  
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. 
 


 
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This definition includes any event resulting from use error or from intentional misuse of 
the investigational or study medical device. 
9.1.4 Serious Adverse Device Effect (SADE):  
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
9.1.5 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 version of the Instructions for Use or Risk Management 
Report. 
To further clarify, an Anticipated SADE (ASADE) is considered an effect which by its 
nature, incidence, severity or outcome has been previously identified in the Instructions 
for Use or Risk Management Report. 
 
9.2 Adverse Event Device Relatedness 
Based on clinical judgment, the Investigator must provide a determination of the 
relationship between the use of the medical device (including the medical procedure) 
and the occurrence of each adverse event according to the following categories:  
 
• Causal Relationship (Definite) – The adverse event is clearly related to the study 
device: the event has a temporal relationship to the study device, follows a known 
pattern of response, or is otherwise logically related to the study device, and no 
alternative cause is present. 
 
• Probable – The adverse event is likely related to the study device: the event has a 
temporal relationship to the study device, follows a known or suspected pattern of 
response, or is otherwise logically related to the study device, but an alternative 
cause may be present. 
 
• Possible – The adverse event is unlikely related to the study device: the event does 
not follow a clear temporal relationship to the study device or does not follow a 
known pattern of response, or is otherwise possibly to be due to the subject’s clinical 
state or other modes of therapy.  
  
In some cases, the adverse event may not be adequately assessed because 
information is insufficient or contradictory and/or the data cannot be verified or 
supplemented.  Maximum effort will be made to define and categorize the event and 
avoid these situations.  If relatedness remains uncertain, then classify the event as 
“possible”. 


 
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• Unlikely – The adverse event can be reasonably explained by another cause 
and/or the relationship with the use of the device seems not relevant, but additional 
information may be obtained. 
 
• Not Related – The adverse event is clearly not related to the study device: the 
event has no temporal or other relationship to the administration of the 
investigational device follows no known or suspected pattern of response, and an 
alternative cause is present. 
9.3 Device Deficiencies 
9.3.1 Definitions  
Device Deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance (includes malfunctions, use errors, 
and inadequate labeling).   
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
Device Malfunction is a failure of the study medical device to perform in accordance 
with its intended purpose when used in accordance with the instructions for use or study 
protocol.  
9.3.2 Reporting   
All device deficiencies and malfunctions will be documented on the case report form, 
reported to the Shockwave Medical Clinical Study manager within 48 hours after the 
designated study site personnel first learns of the event, and reported to the EC/IRB (if 
required) within the EC/IRB required timeframe. 
If a deficiency or malfunction meets the definition of a product complaint (any written, 
electronic, or oral communication that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness, or performance of a device after it is released 
for distribution), a Shockwave Medical Complaint Form will be completed by a 
Shockwave Medical Clinical or Quality representative and entered into the company’s 
complaint log. The Shockwave Medical Quality representative is responsible for 
assessing the need for and submitting any eMDR and/or Vigilance reports, if required.  
Additionally, any IN.PACT DCB device deficiency or malfunction should be reported to 
that device’s manufacturer.  


 
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9.4 Adverse Event Reporting Requirements 
9.4.1 AE Reporting Requirements 
All AE information will be collected from enrollment through 24 months post-procedure 
for subjects in the randomized study. For subjects in the observational study, AEs will 
be collected through hospital discharge.  
AEs should be reported in the subject’s medical records and on the study adverse event 
case report forms (CRF). Data reported should include date of onset, treatment, 
resolution, and an assessment of both seriousness and relationship to the study device. 
AEs will be followed until the event has resolved. 
Any AEs that meet EC/IRB reporting requirements must also be reported to the EC/IRB 
per the institution’s policy. 
9.4.2 SAE Reporting Requirements 
Any AE meeting any of the criteria for an SAE occurring at any time during the study 
must be reported to the Shockwave Medical Clinical Study Manager within 48 hours 
after the designated study site personnel first learns of the event. The SAE must also be 
reported to the EC/IRB per the institution’s policy for reporting SAEs. SAEs should be 
reported in the subject’s medical records and on the adverse event case report forms 
(CRF). Data reported should include date of onset, treatment, resolution, and an 
assessment of relationship to the study device. SAEs will be followed until the event has 
resolved (in the case of permanent impairment, the event will be followed until it 
stabilizes and the overall clinical outcome has been ascertained). 
 
The Investigator must adhere to the following criteria in the case of serious adverse 
events: 
 The Investigator or Co-Investigator must sign the Adverse Event Form(s). 
 It is the responsibility of the Investigator to inform their EC/IRB of serious 
adverse events as required by their EC/IRB procedures.  The Investigator 
should forward a copy of this report to the Sponsor and file in the site 
regulatory binder. 
9.4.3 ADE Reporting Requirements 
All ADE information (including ADEs and SADEs) will be collected from enrollment 
through 24 months post procedure for the randomized study, and through hospital 
discharge for the observational study. ADEs will be recorded in the subject’s medical 
records and on the adverse event case report forms (CRF). Each ADE must be 
evaluated to determine if the event meets the definition of serious adverse device 
effects. ADEs should be reported in the subject’s medical records and on the adverse 
event case report forms (CRF). Data reported should include date of onset, treatment, 


 
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resolution, and an assessment of both seriousness and relationship to the study device. 
ADEs will be followed until the event has resolved (in the case of permanent 
impairment, the event will be followed until it stabilizes and the overall clinical outcome 
has been ascertained). 
9.4.4 SADE Reporting Requirements 
All ADEs will be evaluated by the Shockwave Medical Clinical Study Manager to 
determine if the ADE meets the definition of a SADE. All SAEs must be reported within 
48 hours after the designated study site personnel first learns of the event. All SAEs and 
SADEs should be reported to the EC/IRB in accordance with their requirements.  
9.4.5 AE and Device Deficiency Reporting Time Frames 
Table 5 summarizes the time sensitive reporting requirements for adverse events and 
device deficiencies. The Shockwave Medical Clinical Study Manager is the Sponsor 
contact person for these reporting requirements. 
 
Table 5.  Investigator Responsibilities for Submitting Clinical Events to Sponsor 
Type of Event 
Process 
Device deficiencies 
(including 
malfunctions)  
Submit within 48 hours after the designated study site 
personnel first learns of the event and to the EC/IRB 
(if required) within the EC/IRB required timeframe.  
Serious adverse 
events  
(SAE, SADE, USADE) 
Submit within 48 hours after the designated study site 
personnel first learns of the event and to the EC/IRB 
within the EC/IRB required timeframe.  
Adverse events  
(AE, ADE) 
Submit to Shockwave Medical as soon as possible 
after Investigator has become aware of the event, and 
to the EC/IRB (if required) within the EC/IRB required 
timeframe. 
 
 
 
 
 


 
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10.0 Investigator Responsibilities 
The role of the principal investigator is to implement and manage the conduct of the 
clinical study at their site, as well as ensure data integrity and the rights, safety and well-
being of the participating subjects.  
10.1  EC/IRB Approval 
The Investigator must obtain EC/IRB approval to conduct the study prior to screening 
any potential subjects, and comply with annual continuing approval requirements. All 
correspondence with the EC/IRB should be maintained in the site’s study files.  
10.2  Informed Consent 
The Investigator is responsible for ensuring that all applicable local, national, 
Declaration of Helsinki, and ISO 14155:2011 requirements for all devices in the study 
are met when completing the informed consent process. It is the responsibility of the 
Investigator to ensure written informed consent from each subject, or the legally 
authorized representative of the subject, is obtained prior to the initiation of any study-
related procedures.  The Investigator  must comply with the requirements specified in 
protocol Section 6.3. 
10.3  Protocol Compliance and Delegation of Authority 
The investigator shall conduct the clinical study in compliance with this study protocol, 
and ensure that an adequate study site team and facilities exist and are maintained and 
documented during the duration of the clinical study. The Investigator must maintain a 
Delegation of Authority Form of appropriately qualified persons to whom the Investigator 
has delegated significant study related duties. 
10.4  Medical Care of Subjects 
The investigator shall 
 Provide adequate medical care to a subject during and after a subject's 
participation in the clinical study in the case of adverse events, as described in 
the informed consent, 
 Inform the subject of the nature and possible cause of any adverse events 
experienced, 
 Inform the subject of any new significant findings occurring during the clinical 
study, including the need for additional medical care that may be required, 
 Provide the subject with well-defined procedures for possible emergency 
situations related to the clinical study, and make the necessary arrangements for 
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 Ensure that clinical records are clearly marked to indicate that the subject is 
enrolled in a particular clinical study, 
 Inform, with the subject's approval or when required by national regulations, the 
subject's personal physician about the subject's participation in the clinical study, 
and 
 Make all reasonable efforts to ascertain the reason(s) for a subject's premature 
withdrawal from the clinical study while fully respecting the subject's rights. 
10.5  Safety Reporting 
The investigator must comply with the safety reporting requirements specified in 
protocol Section 9. 
10.6  Protocol Amendment(s) 
The investigator or clinical site staff will not make any modifications to this protocol or 
the Informed Consent form without prior written approval from the Sponsor.  Sponsor 
and Investigator will agree to all amendments made to the protocol or the Informed 
Consent form.  If protocol changes affect the scientific soundness of the clinical 
investigation, or affect the health, welfare, safety and rights of patients, Investigator 
and/or Sponsor will obtain written approval by the Investigator’s EC/IRB, before 
implementing changes.  All amendments must then be submitted to the local EC/IRB, 
as appropriate for approval.     
10.7  Records Retention 
All study records and documentation must be maintained by the investigator and are 
subject to inspection and copying, and must be retained for a period of two (2) years 
after the study is completed or terminated. The Shockwave Medical Clinical Research 
Department should be contacted if the Investigator plans to leave the study site. An 
Investigator may withdraw responsibility to maintain records for the time required by the 
study protocol by transferring custody to another qualified person willing to accept 
responsibility for them.  
 


 
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11.0  Sponsor Responsibilities 
As the study Sponsor, Shockwave Medical is responsible for the overall conduct and 
quality of the study. Shockwave Medical will ensure that qualified monitors and 
designated personnel are monitoring the study according to the pre-determined 
monitoring plan and that the Informed Consent process is followed per the study site’s 
requirements. The sponsor is responsible for the classification and reporting of adverse 
events and ongoing safety evaluation of the clinical study. 
11.1  Selection and Training of Study Sites 
Investigators will be qualified by education, training and experience to assume 
responsibility for the proper conduct of the clinical investigation. Investigators must 
disclose potential conflicts of interest, including financial, that may interfere with the 
conduct of the clinical investigation or interpretation of results.  
Shockwave Medical and/or its designees are responsible for the training of appropriate 
clinical site personnel, including the Investigator, Sub-Investigator(s), and Research 
Coordinator(s). Initial training will be conducted by Shockwave Medical or its designees 
and will be on-going as required.   
An individual Training Record must be signed and dated by both Shockwave Medical 
and/or its designee conducting the training, and each member of the research team that 
attended the training session before any study activity is performed. Original signed 
training records must be submitted to Shockwave Medical and a copy of each training 
record retained in the study Regulatory Binder.  
11.2  Monitoring of Study Sites 
Clinical data from the randomized controlled study will be monitored. Data from the 
observational study will be collected via the electronic data capture system, but will not 
be monitored by the Sponsor or Sponsor designee.   
11.2.1 Randomized Study Monitoring Methods 
Monitoring functions will be conducted by Shockwave Medical and/or its designated 
CRO.  Specific monitoring requirements are detailed in the study specific Monitoring 
Plan maintained in the Shockwave Medical and CRO clinical study project files.   
All monitoring activities shall be documented in a written report to the sponsor. 
Corrective action will be taken to resolve any issues of noncompliance.  If Shockwave 
Medical finds that an Investigator is not complying with the executed Investigator 
Agreement, the study protocol, the applicable laws and regulations, or the requirements 
of the reviewing EC/IRB, prompt action will be taken to secure compliance.  Shockwave 
Medical will reserve the right to suspend or terminate the participation of the Investigator 
or the study site. 


 
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11.2.2 Randomized Study Monitoring Visits  
Scheduled monitoring visits to the clinical study site may occur at the following times: 
prior to the start of the study, interim visits throughout the clinical study as required 
(annually at a minimum), and upon completion of the clinical study. For interim site visits 
100% of source documents must be made available to the monitors. Sites that enroll 
rapidly may be visited more frequently at Shockwave Medical’s discretion. A final Close-
Out Visit will be conducted upon completion of the entire clinical study or at the time a 
site is terminated. 
11.3 Study Deviations 
A study deviation is defined as an instance(s) of failure to follow, intentionally or 
unintentionally, the requirements of the study protocol, applicable laws or regulations, or 
the Investigator Agreement. No deviation from the protocol will be implemented by an 
Investigator without the prior review and approval by Shockwave Medical.  Such 
approval will be documented in writing and maintained in the study files. The 
Investigator must document and notify Shockwave Medical of any deviation from the 
study protocol as soon as possible.  Requests for deviations, and reports of deviations, 
if the deviation affects the subject’s rights, safety and well-being, or the scientific 
integrity of the clinical investigation will be reported to the EC/IRB, as required by their 
procedures.   
Major deviations include those that involve the primary endpoint, the informed consent 
process and the inclusion/exclusion criteria of the study, or any deviation that involves 
or leads to a serious adverse event in a study participant.   
Under certain circumstances, deviations from the study protocol to protect the rights, 
safety and well-being of human subjects may proceed without prior approval of the 
Sponsor and the EC/IRB.  Such deviations shall be documented in writing, and reported 
to the Sponsor and the EC/IRB as soon as possible, and no later than 5 working days. 
Subject specific deviations will be reported on the Protocol Deviation Case Report form. 
Investigators will also adhere to procedures for reporting study deviations to their 
EC/IRB in accordance with their requirements. Deviations from clinical protocol will be 
reviewed and evaluated by Shockwave Medical on an ongoing basis and, as necessary, 
appropriate corrective actions put into place.  
11.4 Device Use Information 
Confirmation that all participating sites will have an available inventory of the study 
devices will be obtained by Shockwave Medical prior to study start. Devices will be 
stored and dispensed as per the participating institutions’ procedures. Device identifiers 
for both the Lithoplasty device and the Admiral IN.PACT DCB will be recorded on case 
report forms.   


 
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11.5 Study/Site Suspension or Early Termination 
The sponsor may suspend or prematurely terminate the study at either an individual site 
or the entire clinical study for significant and documented reasons. A principal 
investigator, EC/IRB, or regulatory authority may suspend or prematurely terminate 
participation in a clinical study at the sites for which they are responsible. 
If suspicion of an unacceptable risk to subjects arises during the clinical study, or when 
so instructed by the EC/IRB or regulatory authorities, the sponsor shall suspend the 
clinical study while the risk is assessed. The sponsor shall terminate the clinical study if 
an unacceptable risk is confirmed. 
Shockwave Medical shall consider terminating or suspending the participation of a 
particular study site or investigator in the clinical study if monitoring or auditing identifies 
serious or repeated deviations on the part of an investigator. If suspension or premature 
termination occurs, the terminating party shall justify its decision in writing and promptly 
inform the other parties with whom they are in direct communication. The principal 
investigator and sponsor shall keep each other informed of any communication received 
from the EC/IRB or any regulatory authority. 
If, for any reason, Shockwave Medical suspends or prematurely terminates the study at 
an individual site, the sponsor shall inform the EC/IRB. If the suspension or premature 
termination was in the interest of safety, the sponsor shall inform all other principal 
investigators. 
If suspension or premature termination occurs, Shockwave Medical will remain 
responsible for providing resources to fulfill the obligations from the study protocol and 
existing agreements for follow up of the subjects enrolled in the clinical study, and the 
principal investigator or authorized designee shall promptly inform the enrolled subjects 
at his/her site, if appropriate. 
Routine close-out activities shall be conducted to ensure that the principal investigator's 
records are complete, all documents needed for the sponsor's files are retrieved, 
remaining clinical study materials are disposed of, previously identified issues have 
been resolved and all parties are notified. 
 
Resumption of a Study after Temporary Suspension: 
When the sponsor completes an analysis of the reason(s) for the suspension, 
implements the necessary corrective actions, and decides to lift the temporary 
suspension, the sponsor shall inform the principal investigators, the EC/IRB, and 
provide them with the relevant data supporting this decision. Concurrence shall be 
obtained from the EC/IRB before the clinical study resumes. If subjects have been 
informed of the suspension, the principal investigator or authorized designee shall 
inform them of the reasons for resumption. 


 
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11.6 Study Completion 
The study is considered completed after all subjects have undergone all of their protocol 
required follow-up visits, all CRFs have been submitted, all queries have been resolved, 
all action items have been closed, and all site payments have been made. All unused 
study materials will be collected and returned to Shockwave Medical or appropriately 
discarded as per instruction. After study closure, a final study report will be completed, 
even if the clinical study was terminated prematurely. 
11.7 
 Audits / Inspections 
Shockwave Medical initiated audits or EC/IRB initiated inspections at the study sites 
may occur during the course of, or after completion of the study.  Access to all study 
records, including source documents, for inspection and duplication may be requested.  
11.8 
Publication Policies  
Publications based on the results of the study will follow the process outlined in the 
Investigator Agreement. During the course of, or at the conclusion of the study, a multi-
center manuscript may be prepared for publication in a reputable peer-reviewed 
scientific journal. The publication of the results from any single site experience within 
the study is not allowed until the preparation and publication of the multi-center results 
has occurred. Exceptions to this rule require the prior approval of Shockwave Medical.   
After publication of the multi-center manuscript, a single site may publish the results of 
its subjects after first complying with the requirements in the Investigator Agreement.  
Any proposed publications must be submitted to Shockwave Medical for review and 
comment at least forty-five (45) days in advance of submitting such proposed 
publications to a publisher or other third party.  If no response is received from 
Shockwave Medical within thirty (30) days of the date submitted, the Investigator may 
proceed with publication as long as all work and research on the clinical study has been 
completed.   
This study is registered with www.clinicaltrials.gov (Identifier NCT02923193). 
11.9 Data Management 
Shockwave Medical and Data Management designees will oversee and/or perform all 
data management functions.  Data management functions include database 
development, system maintenance, user training, data queries, and report generation. 
The principal investigator and/or study staff is responsible for the accuracy and 
completeness of all study data recorded.   
11.9.1 Case Report Forms  
All required data for this study will be collected via web-based electronic data capture 
(EDC) system and entered in electronic Case Report Forms (eCRFs).  


 
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A unique study identifier will be assigned to each study subject. All information recorded 
on the eCRFs about the subject will be recorded using the study identifier. The 
database will contain only the study identifier to identify the subject. The code with 
patient name and study number will be maintained in a secured location. 
11.9.2 Transmission of Data  
For electronic CRFs: 
Required data will be recorded on the appropriate electronic Case Report Forms at the 
time of or as soon as possible after the subject visit.  The eCRFs and any requested 
supporting source documents must be sent to Shockwave Medical and/or retrieved from 
the investigator during monitoring visits.   
11.9.3  Data Queries 
Any data discrepancies identified during data review or a monitoring visit will be queried 
by Shockwave Medical or its designee and must be resolved by the investigational site 
staff and investigator in a timely manner.   
Data audits may be performed for quality assurance of data handling. Any 
discrepancies will be queried by Shockwave Medical or its designee and must be 
resolved by the investigational site staff and investigator in a timely manner, particularly 
during those times data is being prepared for CEC safety reviews and reports required 
by the regulatory authorities. 
11.9.4  Sponsor Data Retention 
Shockwave Medical will retain all study data received for a period of two (2) years after 
the investigation is completed or terminated, or, two (2) years after the records are no 
longer required to support the application to market the device (whichever date is later), 
or longer if required by applicable local regulations. 
 


 
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12.0 STUDY COMMITTEES 
12.1 Clinical Events Committee (CEC) 
To meet the ethical responsibilities and standards for research subjects, an independent 
Clinical Events Committee shall serve as forum for adjudication of any major adverse 
events (MAEs) and target lesion/vessel revascularizations (TLR/TVR) in the randomized 
study. In order to enhance objectivity and reduce the potential for bias, the CEC shall be 
independent of the Sponsor as well as the investigational sites/investigators. 
Observational study AEs will not be adjudicated by the CEC. 
The CEC is made up of clinicians (interventional and non-interventional) with pertinent 
expertise 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.  The 
methodology for performing these responsibilities shall be developed and outlined in the 
CEC Charter. Operational provisions shall be established to minimize potential bias 
(i.e., CEC members shall be blinded to the clinical site to the extent possible during 
adverse event review and adjudication). In the case of an MAE with associated imaging, 
the CEC may review imaging assessments to assess the reported event. 


 
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Confidential – This document is property of Shockwave Medical, Inc. 
13.0 ETHICAL and REGULATORY CONSIDERATIONS 
13.1 Role of Shockwave Medical 
As the Sponsor of this clinical study, Shockwave Medical has the overall responsibility 
for conduct of the study, including assurance that the study will be conducted according 
to the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil October 
2013), applicable EC/IRB requirements, as well as any ISO 14155:2011 and/or national 
requirements. In this study, Shockwave Medical will have certain direct responsibilities 
and may delegate other responsibilities to qualified consultants and/or contract research 
organizations. 
The study will be conducted in Europe, the United States and New Zealand.  
Shockwave Medical will comply with all applicable safety reporting requirements.  
This protocol and any amendments will be submitted to each site’s EC/IRB for formal 
approval of the study.  All subjects considered for this study will be provided a consent 
form describing this study and providing sufficient information for them to make an 
informed decision about their participation.   
13.2 Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical study. A unique subject 
identification code will be assigned and used to allow identification of all data reported 
for each subject.   
Study data may be made available to third parties, e.g., in the case of an audit, 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. 


 
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14.0 Definitions and List of Abbreviations 
14.1  Study Definitions 
Access Site Hemorrhage: Bleeding from the access site which requires transfusion, 
hospitalization (either admission or extended stay), or further treatment for 
management. Hemorrhage, without frank bleeding, needing ≥1 unit RBCs will be 
considered a serious adverse event. 
 
Access Site Infection: Culture-proven wound infection or presumptive treatment with 
antibiotics for clinically diagnosed wound infection. 
 
Acute Renal Failure: Acute post-operative renal insufficiency resulting in one or more 
of the following: (a) increase of >1.0 mg/dl in serum creatinine from most recent prior 
measured level, and current measured absolute value is >2.0 mg/dl; (b) a new 
requirement for dialysis. 
 
Acute PTA failure:  
 Residual stenosis ≥50% by visual estimate,  
 or un-resolved flow-limiting (≥Grade D) dissection, and 
 
Trans-lesional gradient >10 mm Hg is observed. 
 
Adverse Device Effect (ADE): An adverse event related to the use of the medical 
device. This definition includes any event resulting from insufficiencies or inadequacies 
in the instructions for use or the deployment of the device. This definition includes any 
event that is a result of a user error. 
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. This definition includes any event 
resulting from insufficiencies or inadequacies in the Instructions for Use or the 
deployment of the device or any event that is a result of user error. 
NOTE 2: This definition includes any event resulting from use error or from intentional 
misuse of the investigational medical device. 
 
Adverse Event (AE): An adverse event (AE) is 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 device/procedure. 
 
Air Embolism: An inadvertent introduction of air or gas to the vasculature that requires 
medical treatment. 


 
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Allergic Reaction: An allergic reaction characterized by rash, nausea, vomiting, upper 
respiratory congestion, urticaria, shortness-of-breath, vasovagal reaction, or general 
cardiovascular collapse (anaphylaxis). 
 
Amputation (major): Any requirement for amputation above the ankle or higher. 
 
Amputation (minor): Any requirement for amputation below the ankle. 
 
Amputation, Unplanned: An amputation associated with the target limb that occurs 
between the index procedure and 30 days that was not previously planned as part of 
the overall treatment strategy. 
 
Anemia: Decrease from baseline in red blood cells, hemoglobin, or total blood volume 
that is associated with hemodynamic changes or requires transfusion, or a drop in 
hematocrit to below 30%. Any documented anemic event requiring ≥2 units PRBCs will 
be considered an SAE.  
 
Angina: A tight or heavy feeling in the chest, discomfort which spreads from the chest 
to the arm, back, neck, jaw, or stomach, numbness or tingling in the shoulders, arms or 
wrists, shortness of breath, and nausea relieved by rest or nitroglycerine. 
 
Angina, unstable: Chest pain that increases in frequency, intensity, or duration, which 
occurs at rest, or which is new in onset. Unstable angina is a syndrome that is 
intermediate between stable angina and myocardial infarction: it is characterized by an 
accelerating or "crescendo" pattern of chest pain that lasts longer than stable angina, 
occurs at rest or with less exertion than stable angina, or is less responsive to 
medication. Unstable angina and myocardial infarction are considered acute coronary 
syndromes. 
 
Ankle / Brachial Index (ABI): The ratio of systolic blood pressure measured at the 
ankle to systolic blood pressure measured at the brachial artery. 
 
Arterial Occlusion / Thrombosis at Puncture Site: Angiographic or ultrasonographic 
evidence of occlusion at the puncture site limiting antegrade flow to the distal limb. 
 
Arterial Perforation/Rupture/Puncture of an Arterial Wall: Classified as follows: 
Angiographic perforation: Perforation detected by the clinical site at any point during the 
procedure. 
Clinical perforation: Perforation requiring additional treatment (including efforts to seal 
the perforation), or resulting in significant extravasation of blood from the site, abrupt 
closure, limb ischemia or death. 


 
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Arterial Pseudoaneurysm: Disruption of arterial wall confirmed by imaging study and 
requiring intervention. 
 
Arteriovenous Fistula (AVF): An abnormal passage or communication between an 
artery and a vein which may be due to the percutaneous introduction of ancillary 
devices (e.g., needles, catheters, guide wires) confirmed by imaging studies. 
 
Atypical Chest Pain: Located under the sternum, left chest, abdomen, back, or arm 
and is fleeting or sharp. It is unrelated to exercise, not relieved by rest or the 
administration of nitroglycerin. 
 
Bacteremia: Presence of viable bacteria in the circulating blood. May be associated 
with clinical signs/symptoms such as fever. Must be confirmed by having one positive 
blood culture and no subsequent negative cultures. 
 
Bleeding Complication (Major): Bleeding resulting in ≥3 g/dl decrease in hemoglobin 
(if hemoglobin level not available, a decrease in hematocrit of ≥ 10%), or necessitating 
transfusion of >1 unit of PRBC’s /whole blood, or necessitates surgery/endoscopic 
intervention. 
 
Access site: Bleeding from the arteriotomy site which requires transfusion, 
hospitalization (either admission or extended stay), or further treatment for 
management. 
 
Calcification Classification: Calcification must be: 1) on parallel sides of the vessel 
and 2) extending >50% the length of the lesion if lesion is ≥50mm in length; or extending for 
minimum of 20mm if lesion is <50mm in length.   
 
CAPA: Corrective and Preventative Action. 
  
Cardiac Arrhythmia: Electrical disruption of the heart rhythm requiring specific 
medication, defibrillation, or pacemaker insertion to address condition. 
 
Cardiogenic Shock: Subject presents with SBP <80 mm Hg for more than 30 minutes 
unresponsive to fluids or requiring intravenous vasopressor agent or an intra-aortic 
balloon pump (IABP). 
 
Cardiovascular Death: All cardiovascular cause mortality. 
 
Cerebral Vascular Accident (CVA): See Stroke. 
 


 
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Closure, Abrupt: Occurrence of new (during the index procedure), persistent slow, 
reduced, or loss of flow within the target vessel that requires intervention other than the 
index or adjunct treatment. Abrupt closure may also be referred to as acute occlusion if 
there is a total loss of flow. 
 
Closure, Subacute: Target lesion site occlusion that occurs after the index procedure 
is completed (e.g., the subject has left the treatment area) and within 30 days of 
procedure. 
 
Congestive Heart Failure: Documentation of one of the following: a) paroxysmal 
nocturnal dyspnea (PND), b) dyspnea on exertion (DOE) due to heart failure, c) 
elevated PCW with associated SOB or x-ray consistent with congestion. May be related 
to fluid overload in the presence of underlying cardiovascular disease. 
 
Contrast-Induced Nephropathy: Associated with contrast agent resulting in >25% 
increase in serum creatinine or an absolute value of >0.5 mg/dl. 
 
Contrast Media Reaction: An allergic reaction, immediate or delayed, associated with 
the intravascular administration of contrast media that results in symptoms (e.g., itching, 
hives) or physiologic changes requiring treatment (e.g., anaphylactic reaction) or death. 
 
Critical Limb Ischemia: Clinical manifestation of peripheral arterial disease 
characterized by Rutherford Clinical Scale Category of 2-6. (For the purposes of this 
study, only subjects with Rutherford Clinical Scale Category of 2, 3, and 4, are eligible 
for enrollment). 
 
Death: (divided into 2 categories) 
Cardiac death is death due to any of the following: 
1. Acute myocardial infarction. 
2. Cardiac perforation/pericardial tamponade. 
3. Arrhythmia or conduction abnormality. 
4. Stroke within 30 days of the procedure or stroke suspected of being related to the 
procedure 
5. Death due to complication of the procedure, including bleeding, vascular repair, 
transfusion reaction, or bypass surgery. 
6. Any death for which a cardiac cause cannot be excluded. 
Non-cardiac death is a death not due to cardiac causes (as defined immediately 
above). 
 


 
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De novo: A segment of artery that has not previously been treated with angioplasty or 
stenting. 
 
Deep Vein Thrombosis (DVT): Thrombosis of a deep vein, as confirmed by imaging 
study or direct visualization. 
 
Device Deficiency: is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance (includes malfunctions, use errors, 
and inadequate labeling).   
 
Device Malfunction: A malfunction of a device is an unexpected change to the device 
that is contradictory to the Instructions for Use and may or may not affect device 
performance. 
 
Dissection: Disruption of an arterial wall resulting in separation of the intimal layer. May 
or may not be flow limiting. 
 
Dissection Classifications (National Heart, Lung and Blood Institute – NHLBI) 
Type A: Small radiolucent area within the lumen of the vessel disappearing with the 
passage of the contrast material. 
Type B: Appearance of contrast medium parallel to the lumen of the vessel 
disappearing within a few cardiac cycles. 
Type C: Dissection protruding outside the lumen of the vessel persisting after 
passage of the contrast material. 
Type D: Spiral shaped filling defect with our without delayed run-off of the contrast 
material in the antegrade flow. 
Type E: Persistent luminal filling defect with delayed run-off of the contrast material 
in the distal lumen. 
Type F: Filling defect accompanied by total coronary occlusion. 
 
Disseminated Intravascular Coagulation (DIC): A syndrome arising as a complication 
of many different serious and life-threatening illnesses. In its acute form it is a 
hemorrhagic disorder, characterized by multiple ecchymoses, mucosal bleeding, and 
depletion of platelets and clotting factors. Chronic DIC is more subtle and involves 
thromboembolism accompanied by evidence of activation of the coagulation system. 
 
Dizziness: Imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, lightheadedness, unsteadiness, or vertigo. 
 


 
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Drug Reactions: An unwanted or harmful side effect experienced following the 
administration of a drug or combination of drugs and is suspected to be related to the 
drug. 
 
Embolization, Distal: Any distal emboli confirmed by imaging considered to be related 
to the Shockwave Lithoplasty®-treated lesion. 
 
Embolization, Symptomatic: Clinical signs or symptoms of distal emboli detected in 
the treated limb distal to the treated lesion after the index procedure or noted 
angiographically and requiring mechanical or pharmacologic means to improve flow. 
This includes new abrupt occlusions or filling defects. 
 
Femoropopliteal DVT: defined as DVT involvement limited to the superficial femoral or 
popliteal veins, with or without distal (e.g., toward foot) DVT involvement, based on 
duplex ultrasound exam. 
 
Fever: A temperature 38°C (>101.4° F) not related to a culture positive infection. 
 
General Discomfort: Physical or psychosocial signs or symptoms commonly 
associated with hospitalization that are investigated and determined to require minor 
(i.e., aspirin, non-narcotic medication) or no treatment. 
 
Hematoma: Collection of blood (or its degradation products) which exceeds 5 cm in 
diameter, requires treatment, or prolongs hospitalization. 
 
Hemorrhage: Any bleeding which results in a drop in hematocrit from pre-procedure 
level which is associated with hemodynamic compromise or which results in a 
hematocrit of ≤30%, or blood loss that requires transfusion. 
 
Hypertension: Systolic BP >140 mmHg, or diastolic >90 mmHg requiring specific 
medical therapy. 
 
Iliofemoral DVT: Defined as DVT involvement of the common or external iliac veins or 
the common femoral vein, with or without distal (e.g., toward foot) DVT involvement, 
based on duplex ultrasound exam. 
 
Infection, access site: Infection at the vascular access site, documented by lab culture 
or clinical evidence requiring medical treatment (irrigation, debridement, antibiotics, etc.) 
to resolve. 
 
Infection, sepsis: Culture-proven infections or presumptive treatment with antibiotics 
for clinically diagnosed infection. 


 
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Infection, systemic: Systemic infection documented by positive lab culture or clinical 
evidence, requiring medical treatment to treat and resolve. 
 
Intracranial Hemorrhage: Includes all bleeding within the cranium either subarachnoid, 
intra-parenchymal, or intracerebral. 
 
Limb Ischemia: Deficient supply of oxygenated blood to the tissues in the limbs that is 
due to obstruction of the inflow of arterial blood characterized by pain and/or 
discoloration of the limb. 
 
Lithoplasty: Shockwave Medical’s proprietary balloon angioplasty catheter including 
lithotripsy technology that creates pulsatile mechanical energy for disrupting calcified 
vascular plaque. 
 
Lithotripsy: A medical procedure for disrupting calculus in the body. 
 
Luminal Patency: Post-procedure residual stenosis <50% as determined by 
investigator visual assessment or quantitative analysis of the end of procedure 
angiogram. 
 
Major Adverse Event (MAE): For the purposes of this study, the definition of Major 
Adverse Event(s) includes: 
 Need for emergency surgical revascularization of target limb 
 Unplanned target limb major amputation (above the ankle) 
 Symptomatic thrombus or distal emboli that require surgical, mechanical or 
pharmacologic means to improve flow and extend hospitalization 
 Perforations that require an intervention, including bail-out stenting 
 
Myocardial Infarction (MI): Evidence of myocardial necrosis in a clinical setting 
consistent with myocardial ischemia. 
 
Perforation: Puncture of an arterial wall. 
 
Pneumonia: Diagnosed by one of the following: Positive cultures of sputum, blood, 
pleural fluid, emphysema fluid, transtracheal fluid or transthoracic fluid; consistent with 
the diagnosis and clinical findings of pneumonia. Should include chest x-ray diagnostic 
of pulmonary infiltrates. 
 


 
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Procedural Success for randomized study: Procedural success is defined as 
residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or 
stenting by angiographic core lab.  
 
Procedural Success for observational study: Procedural success is defined as final 
residual stenosis ≤30% without flow-limiting dissection (≥ grade D) by angiographic core 
lab. 
 
Pseudoaneurysm: Disruption of the arterial wall characterized by an out-pouching or 
pocket with swirling, flowing blood outside of the confines of the arterial lumen. 
 
Recurrent Occlusion: Occlusion (i.e., total obstruction of vessel lumen) after a 
successful canalization. 
 
Recurrent Thrombosis: Thrombosis (i.e., sub-total obstruction of vessel lumen) 
following successful treatment. 
 
Renal failure (Acute): Acute post-operative renal insufficiency resulting in one or more 
of the following: (a) increase of >1.0 mg/dl in serum creatinine from most recent prior 
measured level, and current measured absolute value is >2.0 mg/dl; (b) a new 
requirement for dialysis. 
 
Renal Insufficiency: An increase in serum creatinine of ≥1.0 mg/dl over previous value 
requiring medical treatment but which does not require dialysis to resolve. 
 
Respiratory Failure: New onset of respiratory insufficiency that requires placement of 
endotracheal tube and/or pneumothorax with or without chest tube. 
 
Respiratory Insufficiency: Deterioration of subject’s respiratory efforts that require 
supportive or medical treatment.  
 
Retroperitoneal bleed: Bleeding into the back of the abdomen from a vascular access 
or puncture site. 
 
Restenosis: Reoccurrence of narrowing or blockage or target lesion. 
 
Rutherford Clinical Category Scale: Clinical scale identifying three grades of 
claudication and three grades of critical limb ischemia ranging from rest pain alone to 
minor and major tissue loss. (ACC/AHA PAD Practice Guidelines – Hirsch et al. 2005) 
 


 
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Grade 
Category 
Clinical Description 
 
0 
Asymptomatic 
I 
1 
Mild claudication 
 
2 
Moderate claudication 
 
3 
Severe claudication 
II 
4 
Ischemic rest pain 
 
5 
Minor tissue loss 
III 
6 
Ulceration or gangrene 
 
Septicemia: One positive blood culture AND clinical evidence for infection (e.g., fever, 
elevated WBC count, hypotension, need for increased inotropic support, end organ 
dysfunction, coagulopathy/ DIC [disseminated intravascular coagulation], need for 
increased ventilator support, etc.). 
 
Serious Adverse Device Effect (SADE): A serious adverse device effect is defined as 
an adverse device effect that results in any of the consequences characteristics of a 
serious adverse event or that might have led to any of these consequences if suitable 
action had not been taken or intervention had not been made or if circumstances had 
been less opportune. 
 
Serious Adverse Event (SAE): A serious adverse event (SAE) is defined an adverse 
event that: 
 led to death, 
 led to a serious deterioration in the health of the subject, that either resulted in: 
o a life-threatening illness or injury, or 
o resulted in a permanent impairment of a body structure or a body function, 
or 
o required 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, or 
o resulted in medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to body structure or a body 
function, or, 
o led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the investigational plan without serious deterioration in health, is not considered a 
serious adverse event.  


 
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Stroke: any neurological deficit lasting 24 hours or longer, or lasting less than 24 hours 
with a brain imaging study showing infarction consistent with deficit. May be further 
categorized as: 
 Ischemic Stroke: neurologic deficit meeting the study definition for Stroke that is 
attributed to thromboembolic event.  
 Hemorrhagic Stroke: neurologic deficit meeting the study definition for Stroke that 
is attributed to bleeding into brain tissue, epidural, subdural, or subarachnoid 
space; or a combination of these sites. 
 
Target Lesion Revascularization, Clinically-driven (TLR): Any revascularization 
(endovascular or surgical) within the target femoropopliteal vessel due to symptoms or 
drop of ABI >20% or >0.15 when compared to the 30-day ABI and associated with an 
angiographic lesion >50% at the target lesion site.  
 
Target 
Vessel 
Revascularization, 
Clinically-driven 
(TVR), 
non-TLR: 
Any 
revascularization (endovascular or surgical) within the target femoropopliteal vessel due 
to symptoms or drop of ABI >20% or >0.15 when compared to the post-procedure 
baseline ABI and associated with an angiographic lesion >50% in the target vessel.  
 
Total Occlusion A 100% stenotic lesion as documented by angiographic absence of 
flow. 
 
Thrombocytopenia: A persistent decrease in the number of blood platelets to 
subnormal levels.  
 
Thrombus: Blood clot that obstructs a blood vessel.  
 
Transient Ischemic Attack (TIA): Focal neurologic abnormalities of sudden onset and 
brief duration (i.e., lasting less than 24 hours and, if an imaging study is performed, 
shows no evidence of infarction).  
 
Toe / Brachial Index (TBI): The ratio of systolic blood pressure measured at the toe to 
systolic blood pressure measured at the brachial artery.  
 
Unanticipated Adverse Device Effect (UADE): An Unanticipated Adverse Device 
Effect (UADE) is defined as any serious adverse effect on health or safety or any life-
threatening problem or death caused by or associated with the device, if that adverse 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the protocol or application (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 


 
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Unanticipated Serious Adverse Device Effect (USADE): A serious adverse device 
effect that has not been expected to occur with the device or during the course of the 
study procedures and has not otherwise been identified as a possible risk in the clinical 
investigations.  
 
Unstable Angina: Angina which increases in frequency, intensity, or duration, which 
occurs at rest, or which is new in onset. Unstable angina is a syndrome that is 
intermediate between stable angina and myocardial infarction: it is characterized by an 
accelerating or "crescendo" pattern of chest pain that lasts longer than stable angina, 
occurs at rest or with less exertion than stable angina, or is less responsive to 
medication. Unstable angina and myocardial infarction are considered acute coronary 
syndromes.  
 
Vascular 
Occlusion 
/ 
Thrombosis 
at 
Puncture 
Site: 
Angiographic 
or 
ultrasonographic evidence of occlusion at the puncture site limiting flow to the limb.  
 
Vasovagal Reaction: Reflex stimulation of the vagus nerve causing slowing of the 
heartbeat, decreased blood pressure, etc. and requires treatment consisting of any of 
the following: (a) >1 liter of IV fluids; (b) postural changes; (c) pacing intervention; or (d) 
administration of atropine. 
 
14.2  List of Abbreviations 
 
ABI 
Ankle brachial index 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CEC 
Clinical Events Committee 
CLI 
Critical Limb Ischemia 
CRF 
Case Report Form 
CTO 
Chronic total occlusion 
DCB 
Drug Coated Balloon 
DUS  
Duplex Ultrasound 
EC 
Ethics Committee 
IFU 
Instructions for use 


 
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ISR 
In Stent Restenosis 
ITT 
Intent-to-Treat 
IRB 
Institutional Review Board 
MAE 
Major adverse event 
OTW 
Over the wire 
PAD 
Peripheral artery disease 
PP 
Per Protocol 
PTA 
Percutaneous transluminal angioplasty 
SADE 
Serious Adverse Device Effect 
SAE 
Serious adverse event 
SFA 
Superficial femoral artery 
TLR 
Target Lesion Revascularization 
TVR 
Target Vessel Revascularization 
 


 
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15.0 Revision History 
Revision 
Release Date 
DCO # 
Reason for Revision 
Doc Owner 
A 
9/8/2016 
16624 
Initial release. 
G. Sahyun 
B 
12/16/16 
16995 
1. 
Change in procedural flow impacting the 
assessment of primary effectiveness endpoint. 
2. 
Addition of interim analysis increasing sample 
size. 
G. Sahyun 


 
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Revision 
Release Date 
DCO # 
Reason for Revision 
Doc Owner 
C 
8/15/17 
17749 
1. 
General administrative changes and 
corrections throughout document. 
2. 
Addition of observational study. 
3. 
Change the number of sites. 
4. 
Ensure alignment of MAE definition 
throughout document. 
5. 
Remove lower limit of target lesion length for 
angiographic inclusion criteria #11. 
6. 
Add clarification to angiographic inclusion 
criteria #12. 
7. 
Add definition to angiographic inclusion 
criteria #14 for calcification based on lesion 
length. 
8. 
Update general exclusion criteria #12 to be 
more specific.   
9. 
Change angiographic inclusion criteria #17 to 
be more specific. 
10. Change angiographic inclusion criteria #18. 
11. Add clarification to angiographic criteria #24. 
12. Update statistical method for analysis of 
randomized study arm only. 
13. Change minimum sample size for analysis. 
14. Remove language that discusses commercial 
availability. 
15. Add instructions to screening procedures and 
subject selection for the different study arms. 
16. Define observational study inclusion and 
exclusion criteria. 
17. Update schedule of events for discharge to 
match study endpoints. 
18. Add schedule of events for observational 
study. 
19. Update Anticoagulation /Antiplatelet 
Medications for consistency. 
20. Update Angiographic Eligibility Assessment 
table to be consistent with body of the 
protocol. 
21. Update instructions for Lithoplasty procedure 
to be consistent with IFU. 
22. Correct control arm procedures. 
23. Remove specific device sizing instruction. 
24. Add observational study procedure guidance. 
25. Update reporting requirements to include 
observational study. 
26. Include reference to observational study for 
CEC. 
27. Change TLR definition to align with CEC 
charter. 
28. Change TVR definition to align with CEC 
charter. 
P. Phattanagosai 


 
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Revision 
Release Date 
DCO # 
Reason for Revision 
Doc Owner 
D 
4/2/2018 
18447 
1. 
Increase total number of sites from 50 to 60. 
2. 
Increase sample size in randomized portion of 
the trial from 334 to 400. 
3. 
Update sample size justification. 
4. 
Increase sample size in observational portion 
of the trial from 250 to 500. 
5. 
Clarified that enrollment in the observational 
portion of the trial may continue after 
enrollment in the randomized portion of the 
trial has been complete. 
P. Phattanagosai 
E 
11/29/2018 
19140 
1. 
Increase sample size in observational portion 
of the trial from 500 to 1000 
2. 
Update study primary endpoint throughout the 
document. Add requirement of post-treatment 
residual stenosis of ≤30% without flow-limiting 
dissection (≥ grade D) prior to DCB or 
stenting by angiographic core lab. 
B. Greschner 
F 
 10/10/2019 
20009  
1. 
General administrative changes and 
corrections throughout document. 
2. 
Increase sample size in observational study 
from 1000 to 1500. Specify that a minimum of 
200 subjects will be treated with the S4 
Lithoplasty catheter. 
3. 
Update study duration for both randomized 
and observational study to 36 months 
throughout document. 
4. 
Clarify verbiage for Primary Endpoint for 
Observational Study to include time point for 
evaluation by angiographic core lab 
throughout document. 
5. 
Introduce S4 Lithoplasty catheter. 
6. 
Update Schedule of Events and section 6.8.6 
for randomized study with assessments 
required prior to pre-target limb 
revascularization. Widen ABI window to 60 
days and update section 6.6. 
7. 
Remove SOC assessments, Walking 
Impairment Questionnaire and EQ-5D from 
Schedule of Events for observational study. 
Widen ABI window to 60 days and update 
section 6.6.  
8. 
Correct post-dilatation requirements to >30% 
residual stenosis throughout document. 
9. 
Open up Health Economics sub-study to 
subjects enrolled in observational study.  
10. Remove requirement for conducting at least 
50 cases using the second generation 
generator. 
B. Greschner 
 


 
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