SIGNATURE Study : DCB (Legflow) vs POBA in Fempop Arteries

Study Overview
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Brief Summary
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The aim of this study is to demonstrate the superiority in safety and efficacy of the Legflow DCB vs standard uncoated POBA in a randomized controlled (RCT) for treatment of patients with symptomatic peripheral artery disease (PAD) due to stenosis, restenosis or occlusion of the femoral and/or popliteal arteries.

Official Title
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SIGNATURE Study: Post-market, Randomized Controlled, Multicenter, Single Blinded Prospective Trial Investigating the Paclitaxel-Coated Balloon (Legflow DCB) Treatment Versus Uncoated Balloon Angioplasty Treatment for Femoro-popliteal Lesions.

Conditions
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Peripheral Arterial Disease, Superficial Femoral Artery Stenosis, Angiopathy, Peripheral

Participation Criteria
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Eligibility Criteria
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Inclusion criteria Patient is ≥18 years Patient has Rutherford Classification 2,3 or4. Patient has provided written informed consent and is willing to comply with study follow-up requirements. De novo stenotic or occlusive lesion(s) or non-stented restenotic or occlusive lesion(s) occurring >90 days after prior plain old balloon (POBA) angioplasty or >180 days after prior DCB treatment. Target lesion is located between the ostium of the SFA and the end of the P1 segment of the popliteal artery Target vessel diameter ≥ 4 mm and ≤ 7 mm Target lesion must be stenotic or occlusive lesion ≤ 150mm in length (one long lesion or tandem lesions) by investigator's visual estimate. [Note: tandem lesions must have a total length of ≤ 150 mm by visual estimate and be separated by ≤ 30 mm.] Target lesion must have angiographic evidence of ≥ 70 % stenosis by investigator's visual estimation Successful, uncomplicated crossing of the target lesion occurs when the tip of the guidewire is distal to the target lesion without the occurrence of flow-limiting dissection of perforation and is judged by visual inspection to be within the true lumen. Subintimal dissection techniques may be used if re-entry occurs above-the-knee (ATK) and without the use of re-entry devices. Target lesion is located at least 30mm from any stent if target vessel was previously stented. A patent inflow artery free from significant stenosis ((≥50% stenosis) as confirmed by angiography. At least one patent native outflow artery to the ankle or foot, free from significant stenosis (≥ 50 % stenosis) as confirmed by angiography. Exclusion criteria: Acute Limb Ischemia Patient underwent an intervention involving the target vessel within the previous 90 days. Patient underwent any lower extremity percutaneous treatment in the ipsilateral limb using plain old balloon (POBA) angioplasty within the previous 90 days. Patient underwent a percutaneous transluminal angioplasty (PTA) of the target lesion using a DCB within the previous 180 days. Pregnant women or women who are intending to become pregnant. Patient has a life expectancy of less than 1 year Patient has a known allergy to contrast medium that cannot be adequately pre-medicated. Patient is allergic to all anti-platelet treatments Patient is receiving immunosuppressant therapy Patient has platelet count <100.000/mm3 or >700.000/mm Patient has history of gastrointestinal hemorrhage requiring a transfusion within 3 months prior to the study procedure Patient is diagnosed with coagulopathy that precludes treatment with systemic anticoagulation and/or dual antiplatelet therapy (DAPT) Patient has history of stroke within past 90 days Patient has history of myocardial infarction within the past 30 days. Patient is participating in an investigational drug or medical device study that has not completed primary endpoint(s) evaluation or that clinically interferes with the endpoints from this study. Patient has had any major (e.g. cardiac, peripheral, abdominal) surgical procedure or intervention unrelated to this study within 30 days prior to the index procedure or has planned major surgical procedure or intervention within 30 days of the index procedure An intervention in the contralateral limb, planned within 30 days post-index procedure Patient had previous bypass surgery of the target lesion Patient had previous treatment of the target vessel with thrombolysis or surgery Patient is unwilling or unable to comply with procedures specified in the protocol or has difficulty or inability to return for follow-up visits as specified by the protocol Target lesion involves an aneurysm or is adjacent to an aneurysm (within 5 mm) Target Lesion requires treatment with alternative therapy such as stenting, laser, atherectomy, cryoplasty, brachytherapy or re-entry devices Significant target vessel tortuosity or other parameters prohibiting access to the target lesion Presence of thrombus in the target vessel Iliac inflow disease requiring treatment, unless the iliac artery disease is successfully treated first during the index procedure. Success is defined as ≤ 30 % residual diameter stenosis without death or major complications. Presence of an aortic, iliac or femoral artificial graft.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DCB (Legflow .035) group<br>treatment with Drug Coated Balloon angioplasty with the Legflow .035 Paclitaxel Balloon Dilatation catheter. | |
| POBA group<br>treatment with standard POBA (uncoated) angioplasty (type and brand at the physician's discretion) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Efficacy Endpoint: | The primary efficacy endpoint is time to clinically-driven target lesion revascularization (CD-TLR) at 12 months, defined as any reintervention at the target lesion due to symptoms OR drop of ankle brachial index (ABI) > 20 % OR ABI > 0.15 compared to the post-procedural ABI. | 12 months post-procedure | 
| Device- and procedure-related death | Primary Safety Endpoint: Freedom from device- and procedure-related death through 30 days post-index procedure; | 30 days post-procedure | 
| Major target limb amputation and clinically-driven target vessel revascularization | Primary Safety Endpoint: A composite of (2.1) time to major target limb amputation (above-the-ankle (ATA)) through 12 months post-procedure and (2.2) time to clinically-driven target vessel revascularization (CD-TVR) through 12 months post-index procedure | 12 months post-procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute device success | defined as successful delivery, balloon inflation, deflation and retrieval of the intact study device without burst below rated burst pressure | during index procedure | 
| Acute procedural success | Acute procedural success is defined as restoration of the target lesion with ≤30% residual stenosis in the final angiogram. | during index procedure | 
| Secondary safety endpoint at discharge up to 30 days post-index procedure | Secondary safety endpoint is a composite of (3.1) freedom from all cause death (3.2) freedom from major target limb amputation (3.3) freedom from CD-TVR | 30 days post-operative | 
| Sustained clinical improvement at 6-, 12- and 24- months post-index procedure | Clinical improvement is defined as a composite of (4.1) freedom from major target limb amputation, (4.2) freedom from TVR, (4.3) freedom from worsening target limb Rutherford class (compared to baseline) (4.4) freedom from decrease in target limb ankle brachial index (ABI) ≥0.15 (compared to baseline) | 6, 12, 24-months post-procedure | 
| Major Adverse Events (MAEs) at 6-, 12- and 24-months post-index procedure | MAEs are defined as composite of (5.1) all-cause death, (5.2) CD-TVR (5.3) major target limb amputation (5.4) thrombosis at the target lesion | 6, 12, 24-months post-procedure | 
| Primary Patency at 6-, 12- and 24-months | The primary patency is defined as a composite of (6.1) freedom from clinically-driven target lesion revascularization (CD-TLR) (6.2) freedom from binary restenosis (restenosis defined as duplex ultrasound (DUS) peak systolic velocity ratio (PSVR) ≥2.4 or ≥50% stenosis) • For discharge and 12-months: assessed by independent Core Lab | 6, 12, 24-months post-procedure | 
| Target Lesion Revascularization at 6-, 12- and 24-months post-index procedure | defined as a reintervention to maintain or restore the patency in the target lesion. TLR is clinically-driven (CD) when the TLR was needed due to symptoms or drop of ankle brachial index (ABI) of ≥20% or >0.15 when compared to post-procedure. | 6, 12, 24-months post-procedure | 
| Target Vessel Revascularization at 6-, 12- and 24-months post-index procedure | defined as a reintervention to maintain or restore the patency in the target vessel. TVR is clinically-driven (CD) when the TVR was needed due to symptoms or drop of ankle brachial index (ABI) of ≥20% or >0.15 when compared to post-procedure | 6, 12, 24-months post-procedure | 
| Binary restenosis at 6-, 12- and 24-months | defined as a restenosis confirmed by DUS PSVR ≥2.4 or ≥50% stenosis (For 12-month: assessed by Independent Core-Lab) | 6, 12, 24-months post-procedure | 
| Major Target Limb Amputation at 6-, 12- and 24-months | defined as an amputation above the ankle (ATA) in the target limb | 30- days, 6, 12, 24-months post-procedure | 
| Thrombosis at the target lesion at 6-, 12- and 24-months | Thrombosis at the target lesion at 6-, 12- and 24-months | 6, 12, 24-months post-procedure | 
| All-cause death at 6-, 12- and 24-months | All-cause death at 6-, 12- and 24-months | 30- days, 6, 12, 24-months post-procedure | 
| Change in target limb Rutherford Classification from baseline to 6-, 12- and 24-months | Change in Target Limb Rutherford Classification from baseline to 6-, 12- and 24-months | 6, 12, 24-months post-procedure | 
| Change in Target Limb Resting ABI or TBI from baseline to 6-, 12- and 24-months | Change in Target Limb Resting ABI or TBI from baseline to 6-, 12- and 24-months | 6, 12, 24-months post-procedure | 
| Improvement of life quality according to the Walking Impairment Questionnaire (WIQ) and the EQ-5D Questionnaire to baseline at follow-up at 6-, 12- and 24-month. | Improvement of life quality according to the Walking Impairment Questionnaire (WIQ) and the EQ-5D Questionnaire to baseline at follow-up at 6-, 12- and 24-month. | 6, 12, 24-months post-procedure | 
| device- and procedure-related death | Freedom from device- and procedure-related death at discharge, 30 days, 6-, 12- and 24-months | 30- days, 6, 12, 24-months post-procedure |