Prospective, Multi-center, Single-arm Study of the Shockwave Medical M5+ Peripheral Intravascular Lithotripsy (IVL) System in Calcified Peripheral Arteries
Phase: NA
Conditions: Peripheral Arterial Disease, Vascular Disease, Peripheral
Sponsor: Shockwave Medical, Inc.

 
 
 
 
 
Prospective, multi-center, single-arm study of the Shockwave Medical M5+ 
Peripheral Intravascular Lithotripsy (IVL) System in calcified peripheral 
arteries (Disrupt PAD+)  
NCT04585763 
April 22, 2021 
 

 
NO.:  CP 64007  
REV. D 
TITLE:  Disrupt PAD+ Study 
CLASS:  CLINICAL PROTOCOL 
PAGE 1 OF 57 
 
Confidential – This document is property of Shockwave Medical, Inc. 
 
  
 
Prospective, multi-center, single-arm study of the Shockwave Medical M5+ Peripheral  
Intravascular Lithotripsy (IVL) System in calcified peripheral arteries (Disrupt PAD+) 
 
Protocol Number: CP 64007 
 
Protocol Date: 22 April 2021 
 
Revision: D 
 
Study Device: Shockwave Medical M5+ Peripheral Intravascular Lithotripsy System 
 
Study 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 PROSPECTIVE, MULTI-CENTER, 
SINGLE-ARM STUDY OF THE SHOCKWAVE MEDICAL M5+ PERIPHERAL INTRAVASCULAR LITHOTRIPSY (IVL) 
SYSTEM IN CALCIFIED PERIPHERAL ARTERIES (DISRUPT PAD+). 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. 

 
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Table of Contents 
1.0 INVESTIGATOR SIGNATURE PAGE ............................................................... 5 
2.0 STUDY SUMMARY............................................................................................ 6 
3.0 INTRODUCTION .............................................................................................. 10 
3.1 Background ........................................................................................................... 10 
3.2 Study Rationale ..................................................................................................... 11 
4.0 STUDY DEVICE / TEST ARTICLE DESCRIPTION ......................................... 12 
4.1 Device/Test Article Description ........................................................................... 12 
4.2 Indication for Use ................................................................................................. 12 
5.0 STUDY OBJECTIVES ..................................................................................... 13 
5.1 Primary Endpoint(s) .............................................................................................. 13 
5.2 Secondary Endpoint(s) .......................................................................................... 13 
6.0 STUDY DESIGN .............................................................................................. 14 
6.1 Site Selection ........................................................................................................ 14 
6.2 Number of Subjects............................................................................................... 14 
6.3 Clinical Study Duration ........................................................................................ 14 
7.0 STUDY PROCEDURES ................................................................................... 15 
7.1 Screening............................................................................................................... 15 
7.2 Subject Selection ................................................................................................... 15 
7.2.1 
Inclusion Criteria ....................................................................................15 
7.2.2 
Exclusion Criteria ...................................................................................16 
7.3 Informed Consent.................................................................................................. 17 
7.3.1 
Process for Obtaining Informed Consent ................................................17 
7.3.2 
Subjects Needing Legally Authorized Representative ...........................17 
7.3.3 
Subjects Unable to Read or Write ...........................................................18 
7.3.4 
Addition of New Information .................................................................18 
7.4 Schedule of Events and Evaluations ..................................................................... 19 
7.5 Medications ........................................................................................................... 19 
7.6 Screening/Baseline Procedures ............................................................................. 20 
7.7 Index Procedure .................................................................................................... 20 
7.7.1 
Definition of Enrollment .........................................................................20 
7.7.2 
Index Procedure ......................................................................................20 
7.8 Follow-Up ............................................................................................................. 22 
7.8.1 
Discharge or Within 12-24 Hours Post-Procedure .................................22 
7.8.2 
30-Day Follow-Up ..................................................................................22 
7.8.3 
6-Month Follow-Up ................................................................................23 
7.8.4 
12-Month Follow-Up ..............................................................................23 
7.8.5 
Prior to Target Limb Revascularization ..................................................23 
7.9 Subject Withdrawal ............................................................................................... 24 
7.9.1 
When and How to Withdraw Subjects ....................................................24 
8.0 BENEFITS AND RISKS ................................................................................... 25 
8.1 Benefits ................................................................................................................. 25 
8.2 Risks ...................................................................................................................... 25 

 
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8.3 Mitigation of Risks ............................................................................................... 25 
9.0 DATA ANALYSIS PLAN ................................................................................. 26 
9.1 General Statistical Methods .................................................................................. 26 
9.2 Sample Size Determination................................................................................... 26 
9.3 Populations for Analysis ....................................................................................... 27 
9.4 Handling of Dropouts or Missing Data ................................................................. 27 
10.0 SAFETY EVENTS ............................................................................................ 28 
10.1 Adverse Event Definitions .................................................................................... 28 
10.1.1 
Adverse Event (AE) ................................................................................28 
10.1.2 
Serious Adverse Event (SAE) .................................................................28 
10.1.3 
Adverse Device Effect (ADE) ................................................................28 
10.1.4 
Serious Adverse Device Effect (SADE) .................................................29 
10.1.5 
Unanticipated Adverse Device Effect (UADE) ......................................29 
10.1.6 
Unanticipated Serious Adverse Device Effect (USADE) .......................29 
10.2 Adverse Event Device and Procedure Relatedness .............................................. 29 
10.3 Device Deficiencies .............................................................................................. 30 
10.3.1 
Definitions...............................................................................................30 
10.3.2 
Reporting.................................................................................................30 
10.4 Serious and Non-serious Adverse Event Reporting Requirements ...................... 30 
10.4.1 
AE Reporting Requirements ...................................................................30 
10.4.2 
SAE Reporting Requirements .................................................................30 
10.4.3 
Non-serious ADE Reporting Requirements............................................31 
10.4.4 
SADE Reporting Requirements ..............................................................31 
10.4.5 
UADE/USADE Reporting Requirements ...............................................31 
10.4.6 
AE and Device Deficiency Reporting Time Frames ..............................32 
11.0 INVESTIGATOR RESPONSIBILITIES ............................................................ 33 
11.1 IRB/EC Approval.................................................................................................. 33 
11.2 Informed Consent.................................................................................................. 33 
11.3 Protocol Compliance and Delegation of Authority .............................................. 33 
11.4 Medical Care of Subjects ...................................................................................... 33 
11.5 Safety Reporting ................................................................................................... 34 
11.6 Protocol Amendment(s) ........................................................................................ 34 
11.7 Records Retention ................................................................................................. 34 
12.0 STUDY SPONSOR RESPONSIBILITIES ........................................................ 35 
12.1 Selection and Training of Study Sites ................................................................... 35 
12.2 Monitoring ............................................................................................................ 35 
12.2.1 
Monitoring Methods ...............................................................................35 
12.2.2 
Monitoring Visits ....................................................................................35 
12.3 Study Deviations ................................................................................................... 36 
12.4 Device Accountability .......................................................................................... 36 
12.5 Study/Site Suspension or Early Termination ........................................................ 36 
12.6 Study Completion ................................................................................................. 37 
12.7 Audits / Inspections............................................................................................... 37 

 
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12.8 Publication Policies ............................................................................................... 38 
12.9 Data Management ................................................................................................. 38 
12.9.1 
Case Report Forms ..................................................................................38 
12.9.2 
Transmission of Data ..............................................................................39 
12.9.3 
Data Queries............................................................................................39 
12.9.4 
Study Sponsor Data Retention ................................................................39 
13.0 STUDY COMMITTEES .................................................................................... 40 
13.1 Clinical Events Committee (CEC) ........................................................................ 40 
14.0 ETHICAL AND REGULATORY CONSIDERATIONS ..................................... 41 
14.1 Role of Shockwave Medical ................................................................................. 41 
14.2 Subject Confidentiality ......................................................................................... 41 
15.0 DEFINITIONS AND ABBREVIATIONS ........................................................... 42 
15.1 Study Definitions .................................................................................................. 42 
15.2 List of Abbreviations ............................................................................................ 51 
16.0 BIBLIOGRAPHY .............................................................................................. 52 
17.0 SUBJECT INFORMED CONSENT .................................................................. 54 
18.0 CASE REPORT FORMS ................................................................................. 55 
19.0 REVISION HISTORY ....................................................................................... 56 
 
 
 
 
 
 

 
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1.0 
INVESTIGATOR SIGNATURE PAGE 
 
Study Title: Prospective, multi-center, single-arm study of the Shockwave Medical M5+ Peripheral 
Intravascular Lithotripsy (IVL) System in calcified peripheral arteries 
 
Study Device: Shockwave Medical M5+ Peripheral IVL System 
 
Protocol Revision: D 
 
Protocol Revision Date: 22 April 2021 
 
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 outlined protocol requirements, all attachments, and applicable 
local and Food and Drug Administration regulations. This investigation will be conducted in 
accordance with the ethical principles as noted in the Declaration of Helsinki and with the 
ICH/Good Clinical Practices, and applicable IRB/EC requirements. 
 
 
 
____________________________________________             
Principal Investigator’s Name (print)   
                                
 
 
 
____________________________________________             ___________________ 
Principal Investigator’s Signature                                                 Date 
 

 
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2.0 
STUDY SUMMARY 
 
Study Title:  
Prospective, multi-center, single-arm study of the Shockwave Medical 
M5+ Peripheral Intravascular Lithotripsy (IVL) System in calcified 
peripheral arteries (Disrupt PAD+)  
Study Objective:  
The objective of this study is to assess the safety and performance of 
the Shockwave M5+ Peripheral IVL System to treat calcified peripheral 
arteries in pre-market countries, and to assess continued safety and 
effectiveness in the US.   
Study Device(s):  
Shockwave Medical M5+ Peripheral IVL System 
Indications for Use:  
The Shockwave Medical M5+ Peripheral IVL System is indicated for 
lithotripsy-enhanced, low-pressure balloon dilatation of lesions, 
including calcified lesions, in the peripheral vasculature, including the 
iliac, femoral, ilio-femoral, popliteal, infra-popliteal, and renal arteries. 
This device is not intended for use in coronary, carotid, or 
cerebrovascular arteries. 
Study Design: 
Prospective, multi-center, single-arm study of the M5+ Peripheral IVL 
system to treat calcified peripheral arteries.  
Enrollment: 
A minimum of 40 lesions in up to 40 subjects at up to 10 sites in 
Australia, New Zealand and the US will be enrolled with the aim of 
treating at least 20 target lesions with the 8.0 mm IVL catheter.  A 
maximum of three target lesions may be treated per subject. 
Subject Population: 
Subjects with moderate and severely calcified iliac and femoropopliteal 
artery disease presenting with Rutherford Category 2 to 5. 
Study Duration / Follow-
Up Period: 
Approximately 6 months of enrollment at up to 10 sites in Australia, 
New Zealand and the US.  Study subjects will be followed through 
discharge, 30 days, 6 and 12 months.  Duplex Ultrasound (DUS) 
assessments will be completed at 12 months. Total anticipated study 
duration is 18 months. 
Primary Safety Endpoint 
Major Adverse Events (MAE) at 30 days defined as: 
• 
Need for emergency surgical revascularization of target limb 
• 
Unplanned target limb major amputation (above the ankle)  

 
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• 
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 Performance 
Endpoint: 
• 
Technical success defined as final residual stenosis ≤30% without 
flow-limiting dissection (≥ Grade D) of the lesion by angiographic 
core lab 
Secondary Endpoints: 
• 
IVL Technical success defined as residual stenosis ≤30% without 
flow-limiting dissection (≥ Grade D) of the lesion post-IVL by 
angiographic core lab  
• 
Procedural success defined as final residual stenosis ≤30% without 
any flow-limiting dissection (≥ Grade D) in all target lesions by 
angiographic core lab 
• 
Major Adverse Events (MAE) at 6 and 12 months 
• 
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 
• 
Clinically-driven target lesion revascularization (TLR) at 30 days, 6 
and 12 months 
• 
Ankle-brachial index (ABI) at 12 months, reported as change from 
baseline 
• 
Rutherford Category at 30 days, 6 and 12 months, reported as 
change from baseline 
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, 4 or 5 of the target limb(s).  
5. Estimated life expectancy >1 year.  

 
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6. Subject is intended to undergo treatment with Shockwave M5+  
Peripheral IVL System for de novo lesions of the ilio-femoropopliteal 
arteries.  
 
Angiographic Inclusion Criteria  
7. Single or multiple de novo target lesion(s) located from the common 
iliac to the femoropopliteal artery, in one or both limbs.  
8. Target lesion reference vessel diameter is between 3.5mm and 
10.0mm by visual estimate.  
9. Target lesion is ≥70% stenosis by investigator via visual estimate.  
10. Target lesion length is ≤200mm for lesions 70-99% stenosed. Target 
lesion can be all or part of the 200mm treated zone.  
11. Chronic total occlusion, lesion length is ≤100mm of the total ≤200 
mm target lesion. 
12. Subject has at least one patent tibial vessel on the target leg with 
runoff to the foot, defined as no stenosis >50%.  
13. 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.  
Study Exclusion Criteria: 
General Exclusion Criteria  
1. Rutherford Clinical Category 0, 1, and 6.  
2. Subject has active infection requiring antibiotic therapy.  
3. History of endovascular or surgical procedure on the target limb 
within the last 30 days or planned within 30 days of the index 
procedure. Note: Concomitant IVL treatment to facilitate large bore 
access at the time of procedure is allowed. 
4. Subject in whom antiplatelet or anticoagulant therapy is 
contraindicated.  
5. Subject has known allergy to contrast agents or medications used to 
perform endovascular intervention that cannot be adequately pre-
treated.  
6. Subject has known allergy to urethane, nylon, or silicone.  
7. Myocardial infarction within 60 days prior to enrollment.  
8. History of stroke within 60 days prior to enrollment.  

 
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9. Subject has acute or chronic renal disease defined as serum 
creatinine of >2.5 mg/dL or >220 umol/L, unless on dialysis.  
10. Subject is pregnant or nursing.  
11. Subject is participating in another research study involving an 
investigational agent (pharmaceutical, biologic, or medical device) that 
has not reached the primary endpoint.  
12. 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.  
13. The planned use of specialty balloons, re-entry or atherectomy 
devices in the target lesion(s).  
 
Angiographic Exclusion Criteria  
14. In-stent restenosis within 10mm of the target zone.  
15. Target lesions distal to the popliteal artery.  
16. Evidence of aneurysm or thrombus in target vessel.  
17. No calcium or mild calcium in the target lesion.  
18. Target lesion within native or synthetic vessel grafts.  
19. Subject has more than three target lesions requiring treatment. 
20. Subject has significant non-target lesion (>50% stenosis or occlusion) 
within the target limb (e.g. iliac, common femoral or below-the-knee) 
not successfully treated prior to treatment of the target lesions.  
21. 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.   
Study Statistical Methods: 
Descriptive statistics will be reported. 
Study Sponsor/Study 
Management Contact: 
Shockwave Medical, Inc. 
5403 Betsy Ross Drive 
Santa Clara, CA 95054 
USA 
 
Contact: Lahn Fendelander 
Title: Senior Director, Clinical Affairs 
Telephone: (direct): (339) 927-3402 
Email: lfendelander@shockwavemedical.com 

 
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3.0 
INTRODUCTION 
3.1 Background  
Peripheral arterial disease (PAD) is one of the most common indications of atherosclerotic disease 
and impacts greater than 200 million people globally (Madhavan et al., 2020). PAD is caused by 
the accumulation of plaque in the arteries that do not supply the brain or the heart. The reduced 
blood flow may lead to pain, tissue loss and eventual foot/leg amputation or death. When the 
disease manifests in the peripheral arteries, it is usually indicative of a developing system-wide 
problem with atherosclerosis. If left untreated, PAD may significantly elevate the risk of 
cardiovascular disease morbidity and mortality (Davros, Garra, & Zeman, 1991).  
 
Although it can involve the renal arteries and/or the arteries of the neck or arms, PAD normally 
develops in the lower extremities. Risk factors for PAD include hypertension, 
hypercholesterolemia, diabetes and smoking (Davros et al., 1991). Individuals with PAD are at risk 
for short-term cardiovascular ischemic events and can develop nonhealing wounds, gangrene, or 
may even need amputation in the affected limb (Bashir & Cooper, 2003; Davros et al., 1991). 
Diabetes and kidney disease can also cause clinical complications in individuals with PAD and can 
lead to a greater risk of limb amputations (Davros et al., 1991). The early diagnosis and treatment 
of PAD reduces an individual’s risk of cardio- or cerebrovascular disease morbidity and mortality.  
 
Percutaneous endovascular therapies are being increasingly employed as the primary 
revascularization treatment for disease of the superficial femoral artery and/or popliteal arteries, 
including calcified occlusions (Diamantopoulos & Katsanos, 2014; Jaff et al., 2015; Norgren et al., 
2007; Roberts et al., 2014).  Endovascular therapies include percutaneous angioplasty (PTA), 
nitinol stents, directional and rotational atherectomy, laser atherectomy, drug-eluting stents 
(DES) and drug-coated balloons (DCB) (Norgren et al., 2007).  
 
Unmet needs in the management of PAD are driving the demand for new plaque modification 
tools, including Shockwave Medical’s Peripheral Intravascular Lithotripsy (IVL). Intravascular 
Lithotripsy is a balloon-based technology that targets calcification to “normalize” vessel 
compliance prior to low pressure dilatation. Peripheral IVL is designed to optimize acute gain 
while minimizing acute vessel injury and reducing bail-out stenting. Pooled 30-day study results of 
the Disrupt PAD I and PAD II studies demonstrated compelling effectiveness and safety results of 
IVL 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 (Zeller, 
2016).  The PAD II 12-month results identified that optimal technique (with at least 1.1:1 IVL 
balloon to artery sizing and adequate therapeutic coverage) improves 12-month primary patency, 
resulting in a clinically-driven TLR rate of 8.6% without concomitant DCB or DES (Brodmann, 
Holden, & Zeller, 2018).   
 
The Disrupt PAD III randomized trial is underway and will compare the optimal vessel preparation 
strategy prior to DCB in calcified femoropopliteal arteries.  An interim analysis of the initial 200 
patients treated in the PAD III Observational Study demonstrated consistent acute safety and 

 
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effectiveness outcomes in a real-world population in a variety of calcified peripheral arteries and 
higher disease complexity (Adams et al., 2020).  In addition, an interim analysis of IVL treatment in 
calcified iliac lesions in the PAD III Observational Study demonstrated IVL is safe and effective for 
the treatment of calcified iliac arteries and optimizes large-bore access (Armstrong et al., 2020).   
 
3.2 Study Rationale  
The Shockwave Medical M5 Peripheral IVL Catheter has FDA clearance and CE Mark approval and 
is indicated for lithotripsy-enhanced, low pressure balloon dilatation of calcified, stenotic 
peripheral arteries in patients who are candidates for percutaneous therapy.  In an effort to 
continually optimize IVL therapy, the M5+ Peripheral IVL System represents an iterative catheter 
design change relative to the M5 device which (1) introduces a larger balloon size (8.0 mm), (2) 
extends the catheter working length from 110 cm to 135 cm, and (3) increases the frequency of 
IVL pulse delivery from 1 Hz (1 pulse per second) to 2 Hz (1 pulse per 0.5 seconds for all catheter 
sizes) with the goal of reducing overall procedure time. The objective of this study is to assess the 
safety and performance of the Shockwave M5+ Peripheral IVL System to treat calcified peripheral 
arteries in pre-market countries, and to assess continued safety and effectiveness in the US.  It is 
being conducted as a post-market study in the US following FDA clearance of the M5+ catheter 
and as a pre-market study in Australia and New Zealand. 
 
 
 

 
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4.0 
STUDY DEVICE / TEST ARTICLE DESCRIPTION 
4.1 Device/Test Article Description 
The Shockwave Medical M5+ Peripheral IVL Catheter is a proprietary lithotripsy device delivered 
through the peripheral arterial system of the lower extremities to the site of an otherwise difficult 
to treat calcified stenosis.  Energizing the lithotripsy device will generate pulsatile mechanical 
energy within the target treatment site, disrupting calcium within the lesion and allowing 
subsequent dilation of a peripheral artery stenosis using low balloon pressure.  The IVL Catheter is 
comprised of an integrated balloon with an array of integrated lithotripsy emitters for the 
localized delivery of pulsatile mechanical energy.  The system consists of the IVL Catheter, an IVL 
Connector Cable and an IVL Generator.   
 
The M5+ IVL Catheter is available in nine (9) sizes:  3.5 x 60mm, 4.0 x 60mm, 4.5 x 60mm, 5.0 x 
60mm, 5.5 x 60mm, 6.0 x 60mm, 6.5 x 60mm, 7.0 x 60mm, and 8.0 x 60mm.  The M5+ Peripheral 
IVL Catheter is compatible with a 6 or 7 F sheath and has a working length of 135cm. 
 
The Shockwave M5+ Peripheral IVL Catheter shaft contains an inflation lumen, a guidewire 
lumen, and the lithotripsy emitters.  The inflation lumen is used for inflation and deflation of 
the balloon with 50/50 saline/contrast medium.  The guidewire lumen enables the use of a  
0.014” guidewire to facilitate advancement of the catheter to and through the target stenosis.  
The system is designed as ‘Over-the-wire’ (OTW) with 135cm shaft working length, so an 
exchange length (300cm) guidewire is indicated.  The emitters are positioned within the 
balloon working length for delivery of pulsatile mechanical energy.  The balloon is located near 
the distal tip of the catheter.  Two radiopaque marker bands within the balloon denote the 
length of the balloon to aid in positioning of the balloon during treatment.  The balloon is 
designed to provide an expandable segment of known length and diameter at a specific 
pressure.  The proximal hub has one port each for inflation/deflation of the balloon, guidewire 
lumen, and connection to the IVL Connector Cable. 
 
The IVL 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 IVL Generator are non-sterile, 
reusable medical devices.  
Refer to the Instructions for Use (IFU) provided for a complete product description. 
4.2 Indication for Use 
The Shockwave Medical M5+ Peripheral IVL System is indicated for lithotripsy-enhanced, low-
pressure balloon dilatation of lesions, including calcified lesions, in the peripheral vasculature, 
including the iliac, femoral, ilio-femoral, popliteal, infra-popliteal, and renal arteries. This device is 
not intended for use in coronary, carotid, or cerebrovascular arteries. 

 
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5.0 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and performance of the Shockwave M5+ Peripheral IVL 
System to treat calcified peripheral arteries in pre-market countries, and to assess continued safety and 
effectiveness in the US.   
5.1 Primary Endpoint(s) 
Primary Safety Endpoint 
Major Adverse Events (MAE) at 30 days 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 Performance Endpoint(s) 
Technical success is defined as final residual stenosis ≤30% without flow-limiting dissection (≥ 
Grade D) of the lesion by angiographic core lab. 
 
5.2 Secondary Endpoint(s) 
Performance 
• 
IVL Technical success is defined as residual stenosis ≤30% without flow-limiting dissection  
(≥ Grade D) of the lesion post-IVL by angiographic core lab. 
• Procedural success is defined as final residual stenosis ≤30% without any flow-limiting 
dissection (≥ Grade D) in all target lesions by angiographic core lab. 
Safety 
• 
MAE at 6 and 12 months 
Patency 
• 
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. Acute PTA failure requiring a stent of the target lesion at any time 
during the index procedure will be counted as a loss of primary patency.  
• 
Clinically driven target lesion revascularization (TLR) at 30 days, 6 and 12 months 
Clinical 
• 
Ankle-brachial index (ABI) at 12 months, reported as change from baseline 
• 
Rutherford Category at 30 days, 6 and 12 months, reported as change from baseline 

 
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6.0 
STUDY DESIGN 
The Disrupt PAD+ study is a prospective, multi-center, single-arm study of the M5+ Peripheral IVL System 
to treat calcified peripheral arteries.   
6.1  Site Selection  
Up to 10 sites located in Australia, New Zealand and the US will participate in the study.  
6.2  Number of Subjects 
A minimum of 40 lesions in up to 40 subjects with moderate and severely calcified iliac and 
femoropopliteal artery disease presenting with Rutherford Category 2 to 5 will be enrolled.  
Each site will be allowed to enroll a maximum of 12 subjects.  Multiple lesion treatment with IVL 
will be allowed and a minimum of twenty (20) lesions across all enrolled subjects must be 
treated with the 8.0 mm catheter size.   
6.3 
Clinical Study Duration 
Enrollment is anticipated to last approximately 6 months.  Study subjects will be followed 
through hospital discharge, 30 days, and 6 and 12 months post-procedure.  Duplex ultrasound 
(DUS) assessments will be completed at 12 months.  Total anticipated study duration is 18 
months. 

 
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7.0 
STUDY PROCEDURES 
7.1 Screening  
Patients presenting to the institution with known iliac and/or femoropopliteal disease requiring 
an interventional procedure will be evaluated for eligibility and participation in the 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) should be performed according to the 
institution’s standard of care.   
Potential subjects will be screened for eligibility.  Written informed consent will be obtained prior 
to any study-specific requirements.  A potential subject will be informed of the elements of the 
study including risks, potential benefits, and required follow-up procedures prior to obtaining the 
potential subject’s informed consent.   
Subjects who meet the clinical inclusion/exclusion criteria will undergo an angiogram.  At the time 
of the angiogram, the subject is considered enrolled if all angiographic eligibility criteria are met, 
and the M5+ peripheral IVL catheter is inserted into the patient. A subject is considered an 
angiographic screen failure if they do not meet angiographic eligibility. Patients who screen failed 
will be documented as such in the electronic data capture (EDC) system.  
7.2 Subject Selection 
7.2.1 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, 4 or 5 of the target limb(s).  
5. Estimated life expectancy >1 year.  
6. Subject is intended to undergo treatment with Shockwave M5+Peripheral IVL System for de 
novo lesions of the ilio-femoropopliteal arteries.  
Angiographic Inclusion Criteria  
7. Single or multiple de novo target lesion(s) located from the common iliac to the 
femoropopliteal artery, in one or both limbs.  
8. Target lesion reference vessel diameter is between 3.5mm and 10.0mm by visual estimate.  
9. Target lesion is ≥70% stenosis by investigator via visual estimate.  
10. Target lesion length is ≤200mm for lesions 70-99% stenosed. Target lesion can be all or part 
of the 200mm treated zone.  

 
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11. Chronic total occlusion, lesion length is ≤100mm of the total ≤200 mm target lesion. 
12. Subject has at least one patent tibial vessel on the target leg with runoff to the foot, defined 
as no stenosis >50%.  
13. 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. 
7.2.2 Exclusion Criteria 
General Exclusion Criteria  
1. Rutherford Clinical Category 0, 1 and 6.  
2. Subject has active infection requiring antibiotic therapy.  
3. History of endovascular or surgical procedure on the target limb within the last 30 days or 
planned within 30 days of the index procedure. Note: Concomitant IVL treatment to facilitate 
large bore access at the time of procedure is allowed. 
4. Subject in whom antiplatelet or anticoagulant therapy is contraindicated.  
5. Subject has known allergy to contrast agents or medications used to perform endovascular 
intervention that cannot be adequately pre-treated.  
6. Subject has known allergy to urethane, nylon, or silicone.  
7. Myocardial infarction within 60 days prior to enrollment.  
8. History of stroke within 60 days prior to enrollment.  
9. Subject has acute or chronic renal disease defined as serum creatinine of >2.5 mg/dL or >220 
umol/L, unless on dialysis.  
10. Subject is pregnant or nursing.  
11. Subject is participating in another research study involving an investigational agent 
(pharmaceutical, biologic, or medical device) that has not reached the primary endpoint.  
12. 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.  
13. The planned use of specialty balloons, re-entry or atherectomy devices in the target lesion(s).  
Angiographic Exclusion Criteria  
14. In-stent restenosis within 10mm of the target zone.  
15. Target lesions distal to the popliteal artery. 
16. Evidence of aneurysm or thrombus in target vessel.  
17. No calcium or mild calcium in the target lesion.  
18. Target lesion within native or synthetic vessel grafts.  

 
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19. Subject has more than three target lesions requiring treatment. 
20. Subject has significant non-target lesion (>50% stenosis or occlusion) within the target limb 
(e.g. iliac, common femoral or below-the-knee) not successfully treated prior to treatment of the 
target lesions. 
21. 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.   
7.3 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 and approved Institutional Review Board 
(IRB)/Ethics Committee (EC) informed consent form (ICF) in order to be eligible for study 
participation.  The informed consent must contain all elements required by 21 CFR Part 50 and 
ISO 14155:2011/ AC: 2011 and comply with the ethical principles of the Declaration of Helsinki.  
7.3.1 
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 IRB/EC, 
• 
The Investigator or designee will provide the subject with a copy of the signed and dated 
informed consent form and any other written information. 
7.3.2 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. 
Please follow the local IRB/EC guidelines on this process. 

 
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7.3.3 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 IRB/EC. 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. 
7.3.4 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 IRB/EC. After approval by 
the IRB/EC, a copy of this information must be provided to the participating subjects, and the 
informed consent process as described above needs to be repeated.  
Please follow the local IRB/EC guidelines on the process of re-consenting subjects. 
 
 

 
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7.4 Schedule of Events and Evaluations 
Table 1 lists the schedule of events and evaluations required for the study. 
Table 1. Study Schedule of Events 
 
Screening/
Baseline2 
Enrollment 
and 
Procedure 
Discharge3 
30 Days4 
(+/- 7 
days) 
6 Months4 
(+/- 30 
days) 
12 Months 
(+/- 30 
days) 
Pre-Target 
Limb 
Revasc 
Informed Consent 
X1 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
Physical Examination  
X 
 
X 
X 
X 
X 
X 
Baseline labs  
X 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
Ankle Brachial Index 
(ABI) 
X 
 
 
X5 
X5 
X 
X 
Rutherford Category 
(RC)  
X 
 
 
X 
X 
X 
X 
Angiographic Lesion 
Assessment  
 
X 
 
 
 
 
X 
IVL Procedure  
 
X 
 
 
 
 
 
Duplex Ultrasound  
 
 
 
 
 
X 
 
Medication regimen 
per protocol  
 
 
X 
X 
X 
X 
X 
Adverse Event 
Assessment  
 
X 
X 
X 
X 
X 
X 
OCT or IVUS (optional) 
 
X 
 
 
 
 
 
1 Consent to be obtained within 30 days prior to procedure.  
2 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.  
3 Examinations are to be completed within 12-24 hours post-procedure or prior to discharge, whichever comes first.  
4 30-Day and 6-month visit can be conducted as an on-site or remote visit. 
5 ABI should be assessed if visit is conducted on-site. 
 
 
7.5 Medications 
Anticoagulation/antiplatelet medications will be administered according to the 2017 European 
Society of Cardiology (ESC) and European Society of Vascular Surgery (ESVS) PAD guidelines 
(Aboyans et al., 2018) and the 2016 American College of Cardiology (ACC) and American Heart 
Association (AHA) PAD guidelines (Gerhard-Herman et al., 2017).  
  

 
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Additional recommendations for anticoagulation and antiplatelet medications include: 
• 
Unfractionated heparin dosing should be undertaken according to hospital standard of 
care. 
• 
Prasugrel or ticagrelor may be used as an alternative to clopidogrel for existing 
management of acute coronary syndrome (ACS). 
• 
Follow antiplatelet and anticoagulation guidelines for the management of patients with 
atrial fibrillation.  
7.6 Screening/Baseline Procedures 
Baseline assessments 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 needed to assess eligibility which are not considered standard of care.  Subjects on 
warfarin or direct thrombin inhibitors should be followed per institutional standard of care by the 
physician.   
Baseline assessments include: 
• 
Medical history  
• 
Physical examination 
o Vital signs 
o Height and weight 
• 
Ankle-brachial index 
• 
Rutherford Category 
• 
Laboratory assessments 
• 
Urine pregnancy test if female of child-bearing age 
7.7 Index Procedure 
7.7.1 Definition of Enrollment 
The definition of enrollment is when the subject signs informed consent, meets all inclusion 
criteria, none of the exclusion criteria, and the IVL catheter has been inserted over a 0.014” 
guidewire which had been previously passed across the study lesion. 
7.7.2 Index Procedure 
Non-target lesions within a limb should be treated successfully prior to treatment of any target 
lesions.  Non-target lesions may be treated with any commercially available device; treating a non-
target lesion with a device that is unapproved or considered investigational will result in a 
protocol deviation.  
 
A full description of the procedure is detailed in the Instructions for Use (IFU). The appropriately 
sized IVL balloon catheter should be selected per the IFU (select a balloon catheter size that is 
1.1:1 based on balloon compliance chart and reference vessel diameter; the largest diameter 

 
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balloon should be used if 1.1:1 sizing is not available).  Once the IVL balloon is placed in the target 
lesion area, the balloon should be inflated to 4 atm and IVL treatment delivered for the pre-
programmed time of 15 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. Table 2 lists the 
pulsing sequence for IVL treatment. 
 
Table 2: IVL System Sequence Chart 
 
 
 
 
 
 
 
 
 
If the operator is unable to pass the IVL balloon through the lesion, a standard PTA balloon up to 
3.0mm may be used for pre-dilatation prior to treatment with the IVL Balloon.  All efforts should be 
made to pass the IVL balloon prior to use of a standard PTA balloon. 
Following delivery of the first IVL cycle (30 pulses), 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 10 seconds to re-establish blood flow.  Repeat the steps above to complete a 
second delivery cycle of 30 pulses to complete a single treatment consisting of 60 pulses.  Additional 
treatment cycles can be performed if deemed necessary. 
If an additional lesion area needs to be treated, follow the treatment steps as identified 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. 
Post-dilatation with a semi or non-compliant PTA balloon catheter should be completed when post-
IVL 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, or 
• 
Trans-lesional gradient >10 mm Hg is observed. 
Follow the angiographic core lab guidelines to complete angiography showing all target lesions 
with reproducible landmarks for follow-up evaluation and assessment. 
Treatment Frequency 
2 Hz  
(1 Pulse every 
0.5 Seconds) 
Maximum Number of 
Continuous Pulses 
(1 cycle) 
30 Pulses 
Minimum Pause Time 
10 Seconds 
Maximum Total Pulses Per 
Catheter 
(10 cycles)  
Displayed on 
generator 

 
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Any commercially approved drug-coated balloon may be used after IVL.  Provisional stenting 
should be performed with a bare metal or drug-eluting stent after primary treatment or post-
dilatation balloon inflations are determined not to be successful.  The angiographic core lab will 
confirm correct use of a stent based on the criteria above for subjects that receive a provisional 
stent.  A provisional stent should be placed for an acute IVL failure defined as: 
• 
Residual stenosis ≥50% by visual estimate, or 
• 
Un-resolved flow-limiting (≥Grade D) dissection, or 
• 
Trans-lesional gradient >10 mm Hg is observed. 
 
Procedural Imaging Requirements 
An angiographic cine image will be obtained for each lesion treated including pre-procedure, post-
IVL and end of procedure.  All angiographic images must be submitted to the core lab for analysis. 
Intravascular imaging (including IVUS or OCT) is optional. If performed, images from the three 
timepoints (pre-procedure, post-IVL and end of procedure) should be submitted to the Study 
Sponsor for analysis. 
 
7.8 Follow-Up 
7.8.1 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: 
• 
Follow up visit assessments including: 
o Physical examination  
▪ 
Vital signs 
▪ 
Height and weight 
▪ 
Target review of symptoms  
o Adverse event assessment 
 
7.8.2 30-Day Follow-Up 
The following evaluations will be performed at 30 days (+/-7 days) post procedure: 
• 
Follow-up visit assessments including: 
o Physical examination 
▪ 
Vital signs 
▪ 
Height and weight 
▪ 
Target review of symptoms 
o ABI (at rest or after exercise; keep consistent with screening) 
o Rutherford Category 
o Review of medications 

 
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o Adverse event assessment 
Note: If the 30-Day Visit cannot be performed on-site, a remote follow-up visit is 
acceptable. If visit is conducted remotely, ABI is not required (will not incur a protocol 
deviation). 
 
7.8.3 6-Month Follow-Up 
The following evaluations will be performed at 6 months (+/-30 days) post procedure: 
• 
Follow-up visit assessments including: 
o Physical Examination 
▪ 
Vital signs 
▪ 
Height and weight  
▪ 
Target review of symptoms 
o ABI (at rest or after exercise; keep consistent with screening) 
o Rutherford Category 
o Review of medications 
o Adverse event assessment 
Note: If the 6-Month Visit cannot be performed on-site, a remote follow-up visit is 
acceptable. If visit is conducted remotely, ABI is not required (will not incur a protocol 
deviation). 
 
7.8.4 12-Month Follow-Up 
The following evaluations will be scheduled for 12 months (+/-30 days) post procedure: 
• 
Follow-up visit assessments including: 
o Physical Examination 
▪ 
Vital signs 
▪ 
Height and weight 
▪ 
Target review of symptoms 
o ABI (at rest or after exercise; keep consistent with screening) 
o Rutherford Category 
o Review of medications 
o Duplex Ultrasound 
o Adverse event assessment 
 
7.8.5 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 
▪ 
Vital signs 
▪ 
Height and weight  
▪ 
Target review of symptoms 
o ABI (at rest or after exercise; keep consistent with screening) 

 
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o Rutherford Category 
o Review of medications 
o Angiographic lesion assessment (Angiographic images for revascularization 
procedures associated with the target limb must be submitted to the core lab.) 
 
7.9 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.  
7.9.1 When and How to Withdraw Subjects 
Subjects may be withdrawn with the medical discretion of the physician, or they may voluntarily 
withdraw their consent at any time without impact to their medical treatment. When a subject is 
withdrawn, all data obtained prior to the time of withdrawal may be submitted to the Study 
Sponsor and be included in the study database, unless otherwise requested by the subject in 
writing. 
In the event a subject is lost to follow-up or cannot be contacted for post-treatment assessments, 
at least three attempts (two phone calls and a certified letter) will be made to locate the study 
subject, and these efforts will be documented. If the subject cannot be located, the subject’s lost 
to follow-up status will be documented in the EDC and they will be exited from the study.  
Should the subject expire, an adverse event and study exit/withdrawal form should be completed. 
Physician assessment is required to determine if the cause of death was possibly or definitely 
related to the M5+ IVL System.  If available, copies of the death certificate and/or an autopsy 
report should be included in the research records. The Investigator may need to provide written 
notification to the IRB/EC upon the death of the study subject, dependent on the IRB/EC policies. 
 

 
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8.0 
BENEFITS AND RISKS 
8.1 Benefits 
There are no guaranteed benefits from participation in the study. The study will provide safety 
and performance data associated with M5+Peripheral IVL System treatment of calcified iliac and 
femoropopliteal arteries. These clinical results may inform physicians in determining the optimal 
treatment strategy for this patient population.  
8.2 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 (IFU) for the M5+Peripheral IVL System. It is important to ensure that the IFU 
referred to represents the generation of the device used in the study procedure.    
8.3 Mitigation of Risks  
Only those patients meeting each inclusion and no exclusion criteria will be enrolled into this 
study. Investigators will be qualified by education, training and experience to assume 
responsibility for the proper conduct of the clinical investigation.  Risks of observed or theoretical 
adverse events will be mitigated through the Instructions for Use, physician training, patient 
selection in the study protocol and close monitoring of protocol adherence. 
All efforts will be made to minimize risks specifically by:  
• Site selection  
• Ensuring compliance to the protocol and IFU 
• Study monitoring 
• Safety processes – protocol adverse event reporting requirements, CEC and data safety 
monitoring committee oversight, and safety reporting to regulatory authorities including 
Vigilance reporting 
 
 

 
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9.0 
DATA ANALYSIS PLAN 
 
9.1 
General Statistical Methods 
Descriptive statistics will be provided in this study.  Analyses will be conducted at pre-specified 
time points including 30 days, 6 and 12 months. 
Categorical data will be summarized using frequency tables, presenting the subject counts and 
percentages. McNemar’s chi-square may be used to assess within-subject changes in a bivariate 
response variable. 
Continuous variables will be summarized by the mean, standard deviation, median, minimum and 
maximum.  Within-subject changes will be analyzed parametrically using the Paired t-test if the 
differences are normally distributed, or non-parametrically using the Sign-Rank Test if the 
differences are not normally distributed. 
Exact confidence intervals will be generated for estimates of proportions.  Asymptotic confidence 
intervals will be generated for estimates of means.  The p-values of all tests will be reported 
without any correction for the multiplicity of tests performed.   
Statistical analyses will be performed using SAS System® Version 9.4. Analyses will be performed 
on all subjects enrolled in the study cohort.  
 
9.2 
Sample Size Determination 
This study will enroll a minimum of 40 lesions in up to 40 subjects at up to 10 sites in Australia, 
New Zealand and the US with the aim of treating at least 20 target lesions with the 8.0 mm IVL 
catheter.  A maximum of three target lesions may be treated per subject. The results from this 
study will provide estimates of the primary and secondary safety and performance endpoints.  
Two-sided 95% Confidence Intervals will be calculated for each endpoint.  
As a confirmatory study, the sample size was justified using methods similar to those that would 
be used to justify a feasibility study. Sample sizes justifications in research and medical device 
development vary with four main methodological approaches: rules of thumb, conceptual 
models, numerical guidelines derived from empirical studies, and statistical formulas (J. Sim, 
Saunders, Waterfield, & Kingstone, 2018). For feasibility studies, the rule of thumb approach is 
most often applied, and sample sizes between 12 and 50 have been recommended (Browne, 
1995; Hertzog, 2008; Julious, 2005; J. Sim & Lewis, 2012; Stallard, 2012).  The sample size for the 
PAD+ study (n=40) is in keeping with these published recommendations and is therefore 
justified. 
 
Assuming a primary performance point estimate of 65% for Procedural Success (derived from 
the PAD III study of peripheral IVL using the M5 catheter) (Gray, 2020), a sample size of 40 
lesions would result in a 2-sided 95% CI of [48.3,79.4]. The lower bound of this interval is similar 

 
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to the PTA (control) arm of PAD III study (50.4%)  (Gray, 2020), which is sufficient given the aims 
of the research. 
 
These data provide reasonable evidence of safety and performance. 
 
9.3 
Populations for Analysis 
Intent-To-Treat Cohort (ITT): All subjects who are enrolled in the study and where delivery of the 
IVL treatment is attempted are included in the ITT Cohort.   
The primary analysis population will be the Intent-to-Treat cohort.  
 
9.4 
Handling of Dropouts or Missing Data 
No imputation of or adjustments for missing data will be performed for the primary analyses. All 
available data will be presented.  For time to event analyses, subjects will be censored at their last 
known follow-up. 

 
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10.0 SAFETY EVENTS 
Standard definitions and reporting requirements for reportable adverse events for the study are 
provided below.  
 
Note: For any of the Adverse Event Definitions listed below, diagnosis should be reported versus 
individual symptoms leading to diagnosis. 
10.1  
Adverse Event Definitions 
10.1.1 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.  
Note: This definition includes events related to the investigational medical device. 
Note: This definition includes events related to the procedures involved. 
10.1.2 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. 
10.1.3 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.  
Note: This definition includes adverse events resulting from insufficient or inadequate Instructions 
for Use, deployment, implantation, installation, or operation, or any malfunction of an 
investigational medical device.  
Note: This definition includes any event resulting from insufficiencies or inadequacies in the 
Instructions for Use, deployment of the device or any event that is a result of user error or 
intentional abnormal use of an investigational medical device.  

 
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10.1.4 Serious Adverse Device Effect (SADE)  
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
10.1.5 Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect is any serious adverse effect on health or safety, any life-
threatening problem or death caused by, or associated with a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the protocol or 
application; or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 21 CFR 812.3(s) 
10.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the clinical investigations or Instructions for Use. 
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 clinical investigations and 
Instructions for Use. 
10.2 Adverse Event Device and Procedure Relatedness 
Based on clinical judgment, the Investigator must provide a determination of device and 
procedure relationship for adverse events 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”. 
•  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. 

 
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•  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. 
10.3 Device Deficiencies 
10.3.1 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.  
10.3.2 Reporting   
All device deficiencies and malfunctions will be documented on the case report form and reported 
to the Study Sponsor within 48 hours after the designated study site personnel first learns of the 
event, and reported to the IRB/EC (if required) within the IRB/EC 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, or performance of a device after it is released for distribution), a Shockwave 
Medical Complaint Form will be completed by a Shockwave representative and entered into the 
company’s complaint system. The Shockwave Medical Quality representative is responsible for 
assessing the need for and submitting any Vigilance and/or Medical Device Reporting (MDR) 
reports, if required.  
10.4 Serious and Non-serious Adverse Event Reporting Requirements 
10.4.1 AE Reporting Requirements 
All AE information will be collected from enrollment through 12 months follow-up. 
AEs should be reported in the subject’s medical records as applicable and on the Adverse Event 
Case Report Form (AE CRF). Data reported should include date of onset, treatment, resolution, 
and an assessment of both seriousness and relationship to the study device and procedure. AEs 
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). 
Any AEs that meet IRB/EC reporting requirements must be reported per the institution’s policy. 
10.4.2 SAE Reporting Requirements 
Any AE meeting any of the criteria for an SAE occurring at any time during the study (enrollment 
through 12 months) must be reported to the Study Sponsor within 48 hours after the designated 
study site personnel first learns of the event. The SAE must also be reported to the IRB/EC per the 
institution’s policy for reporting SAEs. SAEs should be reported in the subject’s medical records as 

 
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applicable and on the Adverse Event Case Report Form (AE CRF). Data reported should include 
date of onset, treatment, resolution, and an assessment of both seriousness and relationship to 
the study device and procedure. 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). 
It is the responsibility of the Investigator to inform their IRB/EC of serious adverse events as 
required by their IRB/EC policies.  The Investigator should forward a copy of this report to the 
Study Sponsor and file in the site regulatory binder. 
 
If the device is suspected to have caused or contributed to the SAE, a Shockwave Medical 
Complaint Form will be completed by a Shockwave representative and entered into the 
company’s complaint system. The Shockwave Medical Quality representative is responsible for 
assessing the need for and submitting any Vigilance and/or Medical Device Reporting (MDR) 
reports, if required. 
10.4.3 Non-serious ADE Reporting Requirements 
All ADE information will be collected from enrollment through 12 months.  ADEs will be recorded 
in the subject’s medical records as applicable and on the Adverse Event Case Report Form (AE 
CRF). Each ADE must be evaluated to determine if the event meets the definition of serious 
adverse device effects. Data reported should include date of onset, treatment, resolution, and an 
assessment of both seriousness and relationship to the study device and procedure. 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). All ADEs must be 
reported to the Study Sponsor as soon as possible after the designated study site personnel first 
learns of the event. 
10.4.4 SADE Reporting Requirements 
All ADEs will be evaluated by the Study Sponsor or designee to determine if the ADE meets the 
definition of a SADE. All SADEs must be reported within 48 hours after the designated study site 
personnel first learns of the event. All SADEs should be reported to the IRB/EC in accordance with 
their requirements.  
If the device is suspected to have caused or contributed to the SADE, a Shockwave Medical 
Complaint Form will be completed by a Shockwave representative and entered into the 
company’s complaint system. The Shockwave Medical Quality representative is responsible for 
assessing the need for and submitting any Vigilance and/or Medical Device Reporting (MDR) 
reports, if required. 
10.4.5 UADE/USADE Reporting Requirements 
Investigators are required to submit a report of a USADE to the Study Sponsor as soon as possible, 
but not later than 48 hours after the Investigator first learns of the event and to the IRB/ECs 
within the required timeframe.  Investigators are required to report a UADE to the reviewing 
IRB/EC and the Study Sponsor as soon as possible, but in no event later than 10 working days after 
the Investigator first learns of the effect. 

 
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If the device is suspected to have caused or contributed to the UADE/USADE, a Shockwave 
Medical Complaint Form will be completed by a Shockwave representative and entered into the 
company’s complaint system. The Shockwave Medical Quality representative is responsible for 
assessing the need for and submitting any Vigilance and/or Medical Device Reporting (MDR) 
reports, if required. 
10.4.6 AE and Device Deficiency Reporting Time Frames 
Table  summarizes the time sensitive reporting requirements for serious and non-serious adverse 
events and device deficiencies. The Study Sponsor or designee is the contact person for these 
reporting requirements. 
Table 3. Investigator Responsibilities for  
Submitting Serious and Non-Serious Adverse Events to the Study 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 IRB/EC (if 
required) within the IRB/EC required timeframe.  
Serious adverse events  
(SAE, SADE)  
Submit within 48 hours after the designated study site 
personnel first learns of the event and to the IRB/EC within the 
IRB/EC required timeframe.  
Unanticipated adverse 
device effect (UADE, 
USADE) 
Submit immediately to the Study Sponsor after the designated 
study site personnel first learns of the event and to the IRB/EC 
within the IRB/EC required timeframe. 
Non-serious adverse 
events  
(AE, ADE) 
Submit to the Study Sponsor as soon as possible after study 
personnel has become aware of the event, and to the IRB/EC 
(if required) within the IRB/EC required timeframe. 
 
 
 
 

 
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11.0  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.  
11.1 IRB/EC Approval 
The Investigator must obtain IRB/EC approval to conduct the study prior to screening any 
potential subjects and comply with annual continuing approval requirements. All 
correspondence with the IRB/EC should be maintained in the site’s study files.  
11.2 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 7.3. 
11.3 Protocol Compliance and Delegation of Authority 
The Investigator shall conduct the clinical study in compliance with this study protocol and 
ensure that the study is appropriately staffed with qualified study personnel throughout the 
duration of the study. In addition, the facilities where the study is being conducted must be 
maintained to allow for proper study conduct. Changes to either study staff or facilities must be 
documented. The Investigator must maintain a Delegation of Authority Form of appropriately 
qualified persons to whom the Investigator has delegated significant study related duties. 
11.4 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 emergency treatment,  
• 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 

 
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• 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. 
11.5 Safety Reporting 
The Investigator must comply with the safety reporting requirements specified in protocol Section 
10.0. 
11.6 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 Study Sponsor.  Study 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 Study Sponsor will obtain 
written approval by the Investigator’s IRB/EC, before implementing changes.  All amendments 
must then be submitted to the IRB/local EC, as appropriate for approval.     
11.7 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 Study Sponsor must 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 him/her.  
 

 
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12.0  STUDY 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 Study Sponsor is responsible for the classification and 
reporting of adverse events and ongoing safety evaluation of the clinical study.   
12.1 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 Principal Investigator, Sub-Investigator(s), and Research 
Coordinator(s). Initial protocol and device training will be conducted by Shockwave Medical or 
its designees and will be ongoing as required.   
A 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. A copy of the signed training records must be 
submitted to Shockwave Medical or its designee and the original signed training record(s) 
should be filed in the site’s study Regulatory Binder.  
12.2 Monitoring 
12.2.1 Monitoring Methods 
Monitoring functions will be conducted by Shockwave Medical and/or its designated Contract 
Research Organization (CRO).  Specific monitoring requirements are detailed in the study-
specific Monitoring Plan maintained in the Shockwave Medical and/or the CRO clinical study 
project files.   
All monitoring activities shall be documented in a written report. 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 IRB/EC, 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. 
12.2.2 
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 per the monitoring 
plan, and upon completion of the clinical study. 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.  Restrictions to on-site 

 
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monitoring visits may require that alternative monitoring strategies be implemented including 
use of remote monitoring or risk-based approaches.  
 
12.3 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. 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 IRB/EC, 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 subject.   
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 Study Sponsor and 
the IRB/EC.  Such deviations shall be documented in writing and reported to the Study Sponsor 
and the IRB/EC 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 IRB/EC 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.  
12.4 Device Accountability 
The Study Sponsor will only provide investigational devices to the site once evidence of required 
IRB/EC approval has been provided to the Study Sponsor or designee. 
The Investigator must keep complete, current and accurate records of the receipt, use, or 
disposition of investigational devices.   
12.5 Study/Site Suspension or Early Termination 
The Study 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, 
IRB/EC, 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 IRB/EC or regulatory authorities, the Study Sponsor shall suspend the clinical 
study while the risk is assessed. The Study 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 

 
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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 Study 
Sponsor shall keep each other informed of any communication received from the IRB/EC or any 
regulatory authority. 
If, for any reason, Shockwave Medical suspends or prematurely terminates the study at an 
individual site, the Study Sponsor shall inform the IRB/EC. If the suspension or premature 
termination was in the interest of safety, the Study 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 closeout activities shall be conducted to ensure that the Principal Investigator's records 
are complete, all documents needed for the Study 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 Study Sponsor completes an analysis of the reason(s) for the suspension, implements 
the necessary corrective actions, and decides to lift the temporary suspension, the Study 
Sponsor shall inform the Principal Investigators and the IRB/EC, and provide them with the 
relevant data supporting this decision. Concurrence shall be obtained from the IRB/EC 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. 
12.6 Study Completion 
The study is considered completed after all subjects have undergone all of their protocol 
required follow-up visits, data entry for all eCRFs has been completed, all queries have been 
resolved, all action items have been closed, and all site payments have been made. All unused 
study materials and study devices 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. 
12.7 Audits / Inspections 
Shockwave Medical, regulatory agencies and IRBs/ECs may conduct audits or inspections at the 
study sites 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. 

 
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12.8  Publication Policies  
The Study Sponsor and the study investigators are committed to timely and complete 
dissemination of the study results. Publications based on the results of the study will follow the 
process outlined in the Investigator Agreement. At the conclusion of the study, a multi-center 
manuscript will be prepared for publication in a reputable peer-reviewed scientific journal. The 
principal results will also be presented at a scientific congress.  
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 and anzctr.org.au.   
12.9 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 are responsible for the accuracy and completeness of all study data recorded.  
The Principal Investigator is responsible for confirming the integrity of the data and for full, 
transparent public reporting of the results. Aspects with respect to the management and 
storage of data will also be outlined in the Patient Informed Consent Form for site specific 
factors. 
Shockwave Medical intends to utilize the data obtained from the study for commercial uses 
including publication and / or presentation of results at congresses, regulatory agency 
submissions, continued product development activities and marketing of their vascular 
products.  All data when used in these activities will be in a de-identified format. Data obtained 
during this study will not be utilized in a database without first gaining the consent of 
participants. 
12.9.1 Case Report Forms  
All required data for this study will be collected via cloud-based electronic data capture (EDC) 
system and entered in electronic Case Report Forms (eCRFs).  
All data collected during the study will be de-identified. For this purpose, a unique study 
identifier will be assigned to each study subject. All information recorded on the electronic Case 
Report form (eCRF) about the subject will be recorded including the study identifier. The 
database will contain only the study identifier to identify the subject. The code with subject 

 
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name and study number will be maintained  by the Principal Investigator in a secured location.  
Subjects names will not be released to Shockwave Medical at any stage of the study. 
12.9.2 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 eCRF and any requested supporting source 
documents (including medical imaging files) must be sent to Shockwave Medical and/or 
retrieved from the Investigator during monitoring visits.  Where possible, data sent to 
Shockwave Medical will be done so utilizing a password secured cloud-based system. 
12.9.3 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. 
12.9.4 
Study 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. The data will be retained in a secure, password 
protected database and stored in the United States of America. 

 
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13.0 STUDY COMMITTEES 
13.1 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 certain pre-specified clinical 
event types described in the CEC charter. In order to enhance objectivity and reduce the 
potential for bias, the CEC shall be independent of the Study Sponsor as well as the study sites / 
Investigators.  
The CEC is made up of clinicians 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).  The methodology for performing these responsibilities shall be developed and 
outlined in the CEC Charter. 

 
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14.0 
ETHICAL and REGULATORY CONSIDERATIONS 
14.1 Role of Shockwave Medical 
As the Study 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 ICH 
Good Clinical Practices (GCP), 21 CFR 812, 820, 50, 54, and 56, Declaration of Helsinki, 
applicable IRB/EC requirements, as well as any ISO 14155 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 specific 
federal regulations, international standards, and/or guidelines required to be followed should 
be outlined within the protocol. 
This protocol and any amendments will be submitted to each site’s IRB/EC 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.   
14.2 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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15.0 DEFINITIONS and ABBREVIATIONS 
15.1  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. 
 
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: This definition includes adverse events resulting from insufficient or inadequate Instructions for 
Use, deployment, implantation, installation, or operation, or any malfunction of the investigational 
medical device.  
Note: This definition includes any event resulting from insufficiencies or inadequacies in the Instructions 
for Use, deployment of the device or any event that is a result of user error or intentional abnormal use 
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. 
 
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. 
 

 
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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 nitroglycerin. 
 
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. 
 
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. 

 
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Access site: Bleeding from the arteriotomy site which requires transfusion, hospitalization (either 
admission or extended stay), or further treatment for management. 
 
Calcification Classification (study eligibility): 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.   
 
Calcification Classification (PARC): Calcification will be assessed by the angiographic core lab according 
to the Peripheral Academic Research Consortium (PARC) definition (Patel et al., 2015).  
 
PARC Degree of Lesion Calcification 
Focal 
Degree of lesion calcification 
Mild 
<180° and greater than one-half of the total lesion length 
Moderate ≥180° (both sides of vessel at same location) and less than one-half of 
the total lesion length 
Severe 
>180° (both sides of the vessel at the same location) and greater than 
one-half of the total lesion 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. 
 
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, or c) elevated pulmonary capillary wedge 
pressure (PCWP) with associated shortness of breath (SOB) or x-ray consistent with congestion. May 
be related to fluid overload in the presence of underlying cardiovascular disease. 
 

 
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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, 4, and 5 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). 
 
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. 

 
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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 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. 
 
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 target 
lesion(s). 
 
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. 
 

 
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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. 
 
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. 
 
Intravascular Lithotripsy (IVL), formerly known as Intravascular Lithoplasty: Shockwave Medical’s 
proprietary balloon angioplasty catheter including lithotripsy technology that creates pulsatile 
mechanical energy for disrupting calcified vascular plaque. 
 
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. 
 
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 
 

 
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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. 
 
Procedural Success: 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 of 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 characteristic of a serious adverse event or that might 
have led to any of these consequences if suitable action had not been taken, 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.  
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.  

 
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• 
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): 
A target lesion revascularization performed due to target lesion diameter stenosis ≥50% and either 
evidence of clinical or functional ischemia (e.g., recurrent/progressive life-limiting intermittent 
claudication, claudication unresponsive to medical therapy, CLI) or recurrence of the clinical 
syndrome for which the initial procedure was performed. Clinically driven target lesion 
revascularization occurs in the absence of protocol directed surveillance ultrasound or angiography. 
 
Target Vessel Revascularization, Clinically-driven (TVR), non-TLR: A target vessel revascularization 
performed due to non-target lesion diameter stenosis ≥50% and either evidence of clinical or functional 
ischemia (e.g., recurrent/progressive life-limiting intermittent claudication, claudication unresponsive 
to medical therapy, CLI) or recurrence of the clinical syndrome for which the initial procedure was 
performed. Clinically driven target vessel revascularization occurs in the absence of protocol directed 
surveillance ultrasound or angiography. 
 
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. 
 
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 

 
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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. 
15.2 
List of Abbreviations 
 
ABI 
Ankle-brachial Index 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
CEC 
Clinical Events Committee 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DUS 
Duplex Ultrasound 
EDC 
Electronic Data Capture 
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IVL 
Intravascular Lithotripsy 
MAE 
Major Adverse Event 
OTW 
Over the Wire 
PAD 
Peripheral Artery Disease 
RC 
Rutherford Category 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TLR 
Target Lesion Revascularization 
TVR 
Target Vessel Revascularization 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 

 
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16.0 BIBLIOGRAPHY 
Aboyans, V., Ricco, J. B., Bartelink, M. E. L., Bjorck, M., Brodmann, M., Cohnert, T., . . . Desormais, I. 
(2018). 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in 
collaboration with the European Society for Vascular Surgery (ESVS). Rev Esp Cardiol (Engl Ed), 
71(2), 111. doi:10.1016/j.rec.2017.12.014 
Adams, G., Shammas, N., Mangalmurti, S., Bernardo, N. L., Miller, W. E., Soukas, P. A., . . . Gray, W. A. 
(2020). Intravascular Lithotripsy for Treatment of Calcified Lower Extremity Arterial Stenosis: 
Initial Analysis of the Disrupt PAD III Study. J Endovasc Ther, 27(3), 473-480. 
doi:10.1177/1526602820914598 
Armstrong, E. J., Soukas, P. A., Shammas, N., Chamberlain, J., Pop, A., Adams, G., . . . Bernardo, N. L. 
(2020). Intravascular Lithotripsy for Treatment of Calcified, Stenotic Iliac Arteries: A Cohort 
Analysis From the Disrupt PAD III Study. Cardiovasc Revasc Med, 21(10), 1262-1268. 
doi:10.1016/j.carrev.2020.02.026 
Bashir, R., & Cooper, C. J. (2003). Evaluation and medical treatment of peripheral arterial disease. Curr 
Opin Cardiol, 18(6), 436-443. doi:10.1097/00001573-200311000-00003 
Brodmann, M., Holden, A., & Zeller, T. (2018). Safety and Feasibility of Intravascular Lithotripsy for 
Treatment of Below-the-Knee Arterial Stenoses. J Endovasc Ther, 25(4), 499-503. 
doi:10.1177/1526602818783989 
Browne, R. H. (1995). On the use of a pilot sample for sample size determination. Stat Med, 14(17), 
1933-1940. doi:10.1002/sim.4780141709 
Davros, W. J., Garra, B. S., & Zeman, R. K. (1991). Gallstone lithotripsy: relevant physical principles and 
technical issues. Radiology, 178(2), 397-408. doi:10.1148/radiology.178.2.1987600 
Diamantopoulos, A., & Katsanos, K. (2014). Treating femoropopliteal disease: established and emerging 
technologies. Semin Intervent Radiol, 31(4), 345-352. doi:10.1055/s-0034-1393971 
Gerhard-Herman, M. D., Gornik, H. L., Barrett, C., Barshes, N. R., Corriere, M. A., Drachman, D. E., . . . 
Walsh, M. E. (2017). 2016 AHA/ACC Guideline on the Management of Patients With Lower 
Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 
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Gray, W. (2020). Intravascular lithotripsy for peripheral artery calcification: The Disrupt PAD III 
randomized controlled trial 30-day outcomes. Paper presented at the VIVA 2020, 
https://www.vivaphysicians.org/viva-programming.  
Hertzog, M. A. (2008). Considerations in determining sample size for pilot studies. Res Nurs Health, 
31(2), 180-191. doi:10.1002/nur.20247 
Jaff, M. R., Rosenfield, K., Scheinert, D., Rocha-Singh, K., Benenati, J., Nehler, M., & White, C. J. (2015). 
Drug-coated balloons to improve femoropopliteal artery patency: Rationale and design of the 
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Julious, S. A. (2005). Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical 
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Madhavan, M. V., Shahim, B., Mena-Hurtado, C., Garcia, L., Crowley, A., & Parikh, S. A. (2020). Efficacy 
and safety of intravascular lithotripsy for the treatment of peripheral arterial disease: An 
individual patient-level pooled data analysis. Catheter Cardiovasc Interv, 95(5), 959-968. 
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Norgren, L., Hiatt, W. R., Dormandy, J. A., Nehler, M. R., Harris, K. A., Fowkes, F. G., & Group, T. I. W. 
(2007). Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J 
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Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus 
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941. doi:10.1016/j.jacc.2014.12.036 
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atherectomy and distal embolic protection: final results of the DEFINITIVE Ca(+)(+) trial. Catheter 
Cardiovasc Interv, 84(2), 236-244. doi:10.1002/ccd.25384 
Sim, J., & Lewis, M. (2012). The size of a pilot study for a clinical trial should be calculated in relation to 
considerations of precision and efficiency. J Clin Epidemiol, 65(3), 301-308. 
doi:10.1016/j.jclinepi.2011.07.011 
Sim, J., Saunders, B., Waterfield, J., & Kingstone, T. (2018). Can sample size in qualitative research be 
determined a priori? International Journal of Social Research Methodology, 21(5), 619-634. 
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Stallard, N. (2012). Optimal sample sizes for phase II clinical trials and pilot studies. Statistics in 
Medicine, 31(11-12), 1031-1042. doi:https://doi.org/10.1002/sim.4357 
Zeller, T. (2016). Safety and performance of Shockwave Lithoplasty. Paper presented at the Charing 
Cross, London, UK.  
 

 
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17.0 SUBJECT INFORMED CONSENT 
The subject informed consent template will be provided as a separate attachment. 

 
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18.0 CASE REPORT FORMS 
Draft case report forms will be provided as a separate attachment. 
 
 
 

 
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19.0 REVISION HISTORY 
Revision 
Release Date 
DCO # 
Reason(s) for Revision 
Doc Owner 
A 
9/30/2020 
21051 
Initial release. 
Clinical 
B 
10/7/2020 
21069 
Added longer catheter working length 
to the study rationale; revised 
angiographic inclusion criteria #8 to 
reflect vessel diameter for common 
iliac; added option for intravascular 
imaging to schedule of events and 
procedural discussion; administrative 
changes. 
Clinical 
C 
10/19/2020 
21128 
Updated Index Procedure section 
with additional sizing 
recommendation and revised 
sequence chart based on current IFU;  
corrected visit label in Schedule of 
Events; added explanatory language 
in Data Management section to be in 
compliance with NZ National Ethical 
Standards; removed DSMB reference 
as not applicable, administrative 
changes. 
Clinical 

 
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Revision 
Release Date 
DCO # 
Reason(s) for Revision 
Doc Owner 
D 
4/27/2021 
21704 
• 
Updated study objective to 
indicate that the study is being 
conducted in the US to evaluate 
continued safety and 
effectiveness in a postmarket 
setting with a cleared medical 
device. 
• 
Updated to include US centers 
following FDA clearance of the 
M5+ catheter. 
• 
Clarified use of devices allowed 
for treatment of non-target 
lesion(s). 
• 
Added additional explanatory 
text for sample size 
determination. 
• 
Clarified MDR reporting 
requirements pertaining to 
serious adverse events. 
Clinical