Shockwave Medical Peripheral Lithoplasty System Study for PAD (Disrupt PAD III)

Study Overview
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Brief Summary
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Shockwave Medical Inc. intends to conduct a prospective, multi-center, single blind, randomized (1:1) study of Lithoplasty treatment used in combination with DCB versus standard balloon angioplasty used in combination with DCB to treat moderate and severely calcified femoropopliteal arteries. Assuming that roughly 15% of the subjects will be lost-to-follow-up, a total of up to 400 subjects (200 per treatment arm) will be enrolled in the study at up to 60 sites in Europe, the United States and New Zealand. In addition to the randomized study, an observational study of subjects who do not meet the inclusion/exclusion criteria for the randomized study will be conducted. The objective of the observational study is to assess the real-world acute performance of the Shockwave Medical Peripheral Lithoplasty System in the treatment of calcified, stenotic, peripheral arteries. The observational study is a prospective, multi-center, single arm observational study for subjects who do not meet the inclusion/exclusion criteria of the randomized study. A maximum of 1500 subjects at the same 60 sites will be enrolled in the observational study. Once enrollment in the randomized portion of the study is complete, subjects may continue to be enrolled in the observational study provided they meet OS eligibility criteria. Results for the observational study will be reported in a separate record under NCT05881421.

Detailed Description
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Shockwave Medical Inc. intends to conduct a prospective, multi-center, single blind, randomized (1:1) study of Lithoplasty treatment used in combination with DCB versus standard balloon angioplasty used in combination with DCB to treat moderate and severely calcified femoropopliteal arteries. The Shockwave Medical Peripheral Lithoplasty System is indicated for lithotripsy-enhanced, low-pressure balloon dilatation of calcified, stenotic peripheral arteries in patients who are candidates for percutaneous therapy. Up to 400 subjects at 60 sites in Europe, the United States and New Zealand. Subjects will be followed through discharge, 30 days, and 6, 12 and 24 months. DUS assessments will be completed at 12 and 24 months. Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or stenting by angiographic core lab. Subjects who do not meet the randomized study inclusion and exclusion criteria, but meet the inclusion and exclusion criteria for the observational study may be enrolled in the observational study. The objective of the observational study is to assess the real-world acute performance of the Shockwave Medical Lithoplasty System in the treatment of calcified, stenotic, peripheral arteries.The observational study is a prospective, multi-center, single arm observational study for subjects who do not meet the inclusion/exclusion criteria of the randomized study. A maximum of 1500 subjects at the same 60 sites will be enrolled in the observational study. Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or stenting by angiographic core lab. Enrollment in the observational study is anticipated to last approximately 22 months. Subjects in the observational study will be followed through hospital discharge. Once enrollment in the randomized portion of the study is complete, subjects may continue to be enrolled in the observational study provided they meet OS eligibility criteria. Results for the observational study will be reported in a separate record under NCT05881421.

Official Title
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Randomized Study of the Shockwave Medical Peripheral Lithoplasty® System Used in Combination With DCB Versus Standard Balloon Angioplasty Used in Combination With DCB to Treat Moderate and Severely Calcified Femoropopliteal Arteries

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Device: Shockwave Lithoplasty® Peripheral Lithoplasty System
* Drug: Medtronic IN.PACT (DCB)


Participation Criteria
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Eligibility Criteria
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Randomized Study Arm Eligibility Criteria General Inclusion Criteria Subject is able and willing to comply with all assessments in the study. 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. Age of subject is greater than or equal to 18. Rutherford Clinical Category 2, 3, or 4 of the target limb. Estimated life expectancy >1 year. Subject is a suitable candidate for angiography and endovascular intervention in the opinion of the investigator or per hospital guideline. Subject is intended to undergo treatment with Lithoplasty followed by DCB, or DCB with standard balloon pre-dilatation. Angiographic Inclusion Criteria Target lesion that is located in a native, de novo superficial femoral artery (SFA) or popliteal artery (popliteal artery extends to and ends proximal to the ostium of the anterior tibial artery). Target lesion reference vessel diameter is between 4.0mm and 7.0mm by visual estimate. Target lesion is ≥70% stenosis by investigator via visual estimate. Target lesion length is ≤180mm for lesions 70-99% stenosed. Target lesion can be all or part of the 180mm treated zone. Chronic total occlusion, lesion length is ≤100mm of the total ≤180 mm target lesion. Subject has at least one patent tibial vessel on the target leg with runoff to the foot, defined as no stenosis >50%. 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. General Exclusion Criteria Rutherford Clinical Category 0, 1, 5 and 6. Subject has active infection requiring antibiotic therapy. Planned target limb major amputation (above the ankle). History of prior endovascular or surgical procedure on the index limb within the past 30 days or planned within 30 days of the index procedure. Subject has a known coagulopathy or has bleeding diatheses, thrombocytopenia with platelet count less than 100,000/microliter. Subject in whom antiplatelet or anticoagulant therapy is contraindicated. Subject has known allergy to contrast agents or medications used to perform endovascular intervention that cannot be adequately pre-treated. Subject has known allergy to urethane, nylon, or silicone. Myocardial infarction within 60 days prior to enrollment. History of stroke within 60 days prior to enrollment. History of thrombolytic therapy within two weeks of enrollment. Subject has acute or chronic renal disease defined as serum creatinine of >2.5 mg/dL or >220 umol/L, or on dialysis. Subject is pregnant or nursing. Subject is participating in another research study involving an investigational agent (pharmaceutical, biologic, or medical device) that has not reached the primary endpoint. 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. The use of specialty balloons, re-entry or atherectomy devices. Angiographic Exclusion Criteria In-stent restenosis within 10mm of the target zone. Lesions within 10mm of the ostium of the SFA or within 10mm of the ostium of the anterior tibial artery. Evidence of aneurysm or thrombus in target vessel. No calcium or mild calcium in the target lesion. Target lesion within native or synthetic vessel grafts. Subject has significant stenosis (>50% stenosis) or occlusion of inflow tract before target treatment zone (e.g. iliac or common femoral) not successfully treated. Subject requires treatment of a peripheral lesion on the ipsilateral limb distal to target site at the time of the index procedure. Failure to successfully cross the guidewire across the target lesion; successful crossing defined as tip of the guidewire distal to the target lesion in the absence of flow limiting dissections or perforations. Subjects who do not meet the inclusion/exclusion criteria for the randomized study may satisfy the eligibility criteria for the observational study. Observational Study Eligibility Criteria Inclusion Criteria Subjects intended to be treated with the Shockwave Medical Peripheral Lithoplasty® System for de-novo or restenotic lesions of the femoral, ilio-femoral, popliteal, and infra-popliteal arteries. Subjects presenting with claudication or CLI by Rutherford Clinical Category 2,3,4,5, or 6 of the target limb. Age of subject is > 18. Subject or subject's legal representative have been informed of the nature of the study, agrees to participate, and has signed the approved study consent form. 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. Exclusion Criteria Subjects with any medical condition that would make him/her an inappropriate candidate for treatment with Shockwave Medical Peripheral Lithoplasty® System as per Instructions for Use (IFU) or investigator's opinion. Subject is already enrolled in other investigational (interventional) studies that would interfere with study endpoints.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Procedural Success | Procedural success is defined as residual stenosis ≤30% without flow-limiting dissection (≥ grade D) prior to DCB or stenting by angiographic core lab. | Peri-Procedural, approximately 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Major Adverse Events (MAEs) | 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 | 30 days | 
| Clinical Success ABI | Defined as ankle-brachial index ABI reported at 30 days as change from baseline. The ABI is the ratio of systolic blood pressure measured at the ankle to systolic blood pressure measured at the brachial artery. Ideally, this ratio should be 1.0, but is often less in a subject with peripheral arterial disease. | 30 days | 
| Clinical Success Quality of Life | Defined by Quality of Life assessed by EQ5D questionnaire reported at 30 days as change from baseline. The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The overall summary index (from Shaw et. al.) computed from the 5-dimension sub-scores was applied. It ranges from 0.000 to 1.000; higher scores indicate better patient-reported health status. | 30 days | 
| Clinical Success Rutherford Category | Defined as Rutherford Category reported at 30 days as change from baseline. 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. 0 is asymptomatic and 6 is ulcers/gangrene. | 30 days | 
| Number of Participants With Clinically-driven Target Lesion Revascularization (TLR) | Any revascularization (endovascular or surgical) within the target femoropopliteal vessel due to symptoms or drop of ABI >20% or >0.15 when compared to the 30-day ABI and associated with an angiographic lesion >50% at the target lesion site | 30 days | 
| Number of Participants With Major Adverse Events (MAEs) | 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 | 6 months | 
| Clinical Success Rutherford Category | Defined as Rutherford Category reported at 6 months as change from baseline. 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. 0 is asymptomatic and 6 is ulcers/gangrene. | 6 months | 
| Number of Participants With Clinically-driven Target Lesion Revascularization (TLR) | Any revascularization (endovascular or surgical) within the target femoropopliteal vessel due to symptoms or drop of ABI >20% or >0.15 when compared to the 30-day ABI and associated with an angiographic lesion >50% at the target lesion site | 6 months | 
| Clinical Success ABI | Defined as ankle-brachial index ABI reported at 6 months as change from baseline. The ABI is the ratio of systolic blood pressure measured at the ankle to systolic blood pressure measured at the brachial artery. Ideally, this ratio should be 1.0, but is often less in a subject with peripheral arterial disease. | 6 months | 
| Clinical Success Quality of Life | Defined by Quality of Life assessed by EQ5D questionnaire reported at 6 months as change from baseline. The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The overall summary index (from Shaw et. al.) computed from the 5-dimension sub-scores was applied and ranges from 0.000 to 1.000; higher scores indicate better patient-reported health status. | 6 months | 
| Number of Participants With Primary Patency | Defined as freedom from clinically-driven target lesion revascularization (TLR) and freedom from restenosis determined by duplex ultrasound or angiogram greater than or equal to 50% stenosis. | 12 months | 
| Number of Participants With Major Adverse Events (MAEs) | 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 | 12 months | 
| Number of Participants With Clinically-driven Target Lesion Revascularization (TLR) | Any revascularization (endovascular or surgical) within the target femoropopliteal vessel due to symptoms or drop of ABI >20% or >0.15 when compared to the 30-day ABI and associated with an angiographic lesion >50% at the target lesion site | 12 months | 
| Clinical Success ABI | Defined as ankle-brachial index ABI reported at 12 months as change from baseline. The ABI is the ratio of systolic blood pressure measured at the ankle to systolic blood pressure measured at the brachial artery. Ideally, this ratio should be 1.0, but is often less in a subject with peripheral arterial disease. | 12 months | 
| Clinical Success Rutherford Category | Defined as Rutherford Category reported at 12 months as change from baseline. 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. 0 is asymptomatic and 6 is ulcers/gangrene. | 12 months | 
| Clinical Success Quality of Life | Defined by Quality of Life assessed by EQ5D questionnaire reported at 12 months as change from baseline. The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The overall summary index (from Shaw et. al.) computed from the 5-dimension sub-scores was applied and ranges from 0.000 to 1.000; higher scores indicate better patient-reported health status. | 12 months | 
| Number of Participants With Primary Patency | Defined as freedom from clinically-driven target lesion revascularization (TLR) and freedom from restenosis determined by duplex ultrasound or angiogram greater than or equal to 50% stenosis. | 24 months | 
| Number of Participants With Major Adverse Events (MAEs) | 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 | 24 months | 
| Number of Participants With Clinically-driven Target Lesion Revascularization (TLR) | Any revascularization (endovascular or surgical) within the target femoropopliteal vessel due to symptoms or drop of ABI >20% or >0.15 when compared to the 30-day ABI and associated with an angiographic lesion >50% at the target lesion site | 24 months | 
| Clinical Success ABI | Defined as ankle-brachial index ABI reported at 24 months as change from baseline. The ABI is the ratio of systolic blood pressure measured at the ankle to systolic blood pressure measured at the brachial artery. Ideally, this ratio should be 1.0, but is often less in a subject with peripheral arterial disease. | 24 months | 
| Clinical Success Rutherford Category | Defined as Rutherford Category reported at 24 months as change from baseline. 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. 0 is asymptomatic and 6 is ulcers/gangrene. | 24 months | 
| Clinical Success Quality of Life | Defined by Quality of Life assessed by EQ5D questionnaire reported at 24 months as change from baseline. The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The overall summary index (from Shaw et. al.) computed from the 5-dimension sub-scores was applied and ranges from 0.000 to 1.000; higher scores indicate better patient-reported health status. | 24 months |