SELUTION4SFA Trial

Prospective, multi-center, single blinded, 2:1 randomized, controlled, superiority clinical trial.

This study will enroll up to 300 randomized subjects, and up to 20 subjects in a parallel pharmacokinetic (pK) sub study, at up to 60 clinical sites in the United Stated (US), Europe (EU) and Asia. A minimum of 50% of randomized subjects will be enrolled in the US. No more than 45 subjects (15% of the total randomized cohort) can be enrolled in the randomized cohort at any single investigational site.

Randomized Cohort:

Up to 300 subjects who meet all eligibility criteria will be randomized 2:1 by permuted block method (stratified by site and adjunctive lesion preparation) to one of two treatment arms:

• Intervention - treatment with SELUTION SLR™ 018 DEB
• Control - treatment with commercially available PTA (uncoated balloon)

Pharmacokinetic (pK) Sub-study:

The pK substudy is a parallel registry consisting of up to 20 additional consecutive subjects meeting all eligibility criteria treated with the SELUTION DEB recruited at select study sites. The separate PK substudy protocol details the schedule of evaluations and blood draws to characterize the pK plasma profile of sirolimus.

Clinical Inclusion Criteria:

• Subject age is ≥ 18 years or minimum legal age as required by local regulations.
• Life expectancy >1 year in opinion of investigator.
• Documented ischemia with Rutherford classification category 2, 3 or 4.
• Target lesion(s) in the SFA or PPA.
• Able to walk without the assistance of a walker.
• Subject is willing and able to provide informed consent and comply with study procedures and required follow-up evaluations.
• Female subjects only: If female, then subjects of childbearing potential must have a negative pregnancy test ≤ 7 days before the procedure and be prepared to use effective contraception for 12 months after treatment.

Angiographic Inclusion Criteria:

• Angiographic evidence that target lesion lies within the superficial femoral artery and/or proximal popliteal artery (P1 and P2 only).
• Angiographic evidence that the target lesion consists of either a de novo lesion or a non-stented restenotic lesion, or a combination of both, that meets one of the following criteria:

A. A stenosis of 70-99% with lesion length between ≥3cm and <20cm by visual estimation.

B. A total (100%) occlusion with lesion length between ≥3cm and ≤10cm by visual estimation.

C. A combination lesion (stenosis and total occlusion) must have a total lesion length between ≥3cm and <20cm by visual estimation with an occluded segment that is ≤10cm by visual estimation.

D. If multiple lesions are to be treated, then only 2 lesions may be included. The total combination of lengths must be between ≥3cm and < 20cm by visual estimation, and there must be at least 5 cm of artery that is not to be treated between them.

• Target vessel reference diameter ≥4mm and ≤7mm.
• Patent arterial inflow (common iliac, external iliac, common femoral and profunda femoris arteries, and the proximal 2 cm of the SFA) free from significant lesion (defined as ≥50% stenosis) as confirmed on angiography.

Note: Where required, inflow iliac arteries (common and external iliac arteries only) must be successfully treated during the index procedure. Completion angiography must confirm successful treatment of inflow disease (≤30% residual stenosis, no distal embolization, and no Grade C or greater dissection ) prior to pre-dilation and randomization of the target lesion(s). Drug-eluting devices are not allowed for treatment of the occluded inflow iliac arteries.

• Angiographic evidence of adequate distal run off (defined as ≤50% stenosis) in one or more tibial arteries on initial angiography, and if applicable, after completion of inflow artery treatment.

Note: Treatment of outflow disease is permitted during the index procedure. Drug-eluting devices are not allowed for outflow treatment.

PK Sub-Study Inclusion Criteria:

Subjects must meet all of the main protocol inclusion criteria to participate in the PK sub-study. Subjects must also meet the following additional PK sub-study inclusion criteria:

• Subject is willing and able to provide informed consent for the PK sub-study and comply with the PK sub-study procedures and required follow-up evaluations.

Clinical Exclusion Criteria:

• Other surgical or endovascular procedure in the target limb that occurred within 14 days prior to index procedure or is planned for within 30 days following index procedure, with exception for diagnostic angiography.
• Inability to tolerate dual antiplatelet therapy.
• Known hypersensitivity or allergy to Sirolimus or other pharmacologic agents, such as contrast agent, which are required for the procedure and which cannot be adequately pre-treated.
• Stroke or MI within 3 months of enrollment.
• Symptom onset less than 14 days prior to index procedure (acute limb ischemia).
• Lower limb disease in the contralateral leg that requires treatment at the index procedure, or, that is planned within 14 days prior to the index procedure or within 30 days after the index procedure.
• Prior vascular surgery (including bypass and endarterectomy) of abdominal aorta, iliac arteries, or arteries of the index limb.
• Non-atherosclerotic disease of the index limb (including aneurysmal disease, vasculitis, Buerger's disease)
• Target lesion requires treatment with alternative therapies such as thrombolysis, thrombus aspiration, cutting/scoring/contoured balloon, stenting, laser, cryoplasty, intravascular lithotripsy, brachytherapy, re-entry device).
• Subject has target lesion(s) that require treatment via pedal site.
• Subject has target lesion(s) that require access via upper extremity arteries.
• Hypercoagulable state or disorder present, or coagulopathy present, including platelet count less than 80,000 per microliter.
• Chronic renal insufficiency (dialysis dependent, or serum creatinine >2.5 mg/dL within 30 days of index procedure).
• Systemic infection (WBC > 12,000 and febrile) or known immune compromise.
• Breast-feeding woman.
• Currently participating in another investigational drug or device study that has not completed primary endpoint follow-up.

Angiographic Exclusion Criteria:

• Presence of a previously placed stent in the treated artery.
• Failure to successfully cross the target lesion.
• Residual stenosis ≥30% after pre-dilatation.

PK Sub-Study Exclusion Criteria:

• Subjects must meet none of the main protocol exclusion criteria (Section 6.1.2 of the main protocol) to participate in the PK sub-study. Subjects will be excluded if any of the following additional PK sub-study exclusion criteria are met:
• Any limus family (Zotarolimus, Everolimus, Sirolimus etc.) eluting device has been placed/used in any part of the body within 3 months prior to the index procedure including non-target lesion(s) treated during the index procedure.
• Planned intervention with any limus family (Zotarolimus, Everolimus, Sirolimus etc.) eluting device anywhere in the body within 6 months after the index procedure. Note: staged procedures >30 days after index procedure (Exclusion #20 and #22 of the main protocol) are permitted only in the main protocol, and are not permitted in this PK sub-study.
• The subject is taking or has taken within the last 3 months any limus family medication(s) for any reason.
• Subjects who are taking strong CYP3A4 Inhibitors within 14 days before the index procedure or plan to take the strong inhibitors during the study period. Strong inhibitors include: cobicistat; ritonavir; indinavir and ritonavir; itraconazole; ketoconazole; lopinavir and ritonavir; paritaprevir and ritonavir and ombitasvir (and/or dasabuvir); posaconazole; saquinavir and ritonavir; tipranavir and ritonavir; elvitegravir and ritonavir; telithromycin; voriconazole; ceritinib; clarithromycin; idealalisib; nefazodone; nelfinavir.
• Subjects who are taking strong CYP3A4 Inducers within 14 days before the index procedure or plan to take the strong inducers during the study period. Strong inducers include apalutamide; carbamazepine; enzalutamide; ivosidenib; lumacaftor and ivacaftor; mitotane; phenytoin; rifampin; St. John's wort.