Trial to Assess the Safety and Efficacy of Sirolimus-Coated Balloon vs. Uncoated Standard Angioplasty for the Treatment of Below-the-knee Peripheral Arterial Disease

The purpose of this study is to assess whether efficacy of the MagicTouch® Sirolimus Coated PTA Balloon Catheter (SRL-DCB) is superior and whether safety is non-inferior to Plain Old Balloon Angioplasty (POBA) regarding treatment of high-grade stenoses ≥ 75 % in the infrapopliteal arteries (located below the P3 segment of the popliteal artery to the tibiotalar joint) in patients presenting with chronic limb-threatening ische-mia (CLTI) (Rutherford 4-6).

Inclusion criteria

• Age ≥ 18 years at the time of consent.
• Subject has been informed of the nature of the study, is willing to comply with all required follow-up evaluations within the defined follow-up visit windows and has signed an Ethics Committee (EC) approved consent form.
• Female subjects of childbearing potential have a negative pregnancy test ≤ 7 days before the procedure and are willing to use a reliable method of birth control for the duration of study participation. Female subjects will be exempted from this requirement in case they are sterile, infertile, or have been post-menopausal for at least 12 months (no menses).
• Life expectancy > 1 year in the investigator's opinion.
• Subject presenting with documented chronic limb-threatening ischemia (CLTI) in the target limb defined as Rutherford category 4, 5 or 6.
• In case of Rutherford category 5 or 6: Subjects with documented infection grade ≤ 2 according to the wound ischemia foot infection (WIfI) classification.
• All ischemia grades according to the wound ischemia foot infection (WIfI) classifi-cation are allowed.documented infection grade ≤ 2 according to the wound ischemia foot infection (WIfI) classification.

• All ischemia grades according to the wound ischemia foot infection (WIfI) classification are allowed.

• Reference Vessel Diameter (RVD) ≥ 2 and ≤ 4.0 mm. 9. ≥ 75 % stenosis or occlusion of the target vessel by visual estimate of the treating physician; no minimal lesion length required.

• The target lesion may consist of multiple target vessel lesions, if they are ≤ 5 cm away from each other and if at least one of them is a stenosis ≥ 75 % and all lesions are located in only one of the infrapopliteal arteries or directly within the transition area. Non-target vessels (e.g. inflow lesions or contralateral extremity, other non-target vessels below the knee) and non-target lesions of the target ves-sel can be treated during the study index procedure but according to the patient's randomization result (interventional group: Sirolimus-coated balloon or POBA; control group: only POBA).

• Lesion length < 30 cm, no limitation in number of used devices. 12. The lesion must be located in the infrapopliteal arteries and above the ankle joint. Lesions may not be located above the tibioperoneal trunk or below the tibiotalar joint (arteries of the foot), nor can the treatment (investigational device or standard PTA, including pre-dilatation) extend beyond these indicated regions for more than 1 cm. Note: A target lesion can extend into the P3 segment in case it involves a straight uninterrupted lesion extending from the target vessel.

• Presence of documented run-off to the foot (clearly visible at least one of the following run-off vessels: dorsalis pedis or pedal arch or plantar arteries by angiography). The target vessel should give direct or indirect run-off to the foot.

• Inflow free from flow-limiting lesion confirmed by angiography. Patients with flow-limiting inflow lesions (≥ 50 % stenosis) can be included if the lesion(s) have been treated successfully before enrollment, with a maximum residual stenosis of ≤ 30 % per visual assessment. If an inflow lesion must be treated within or above the P3 segment of the popliteal artery, there must be a minimum of 3 cm healthy tissue between this (treated) lesion and the infrapopliteal target lesion. Use of paclitaxel-coated devices is not permitted.

• Successful pre-dilatation of the (entire) target lesion. Success being documented by angiographic visual estimate of ≤ 50 % residual diameter stenosis of the target lesion and no flow limiting dissection (< Grade D dissection).

• Participants can only be enrolled once with a single target lesion.

Exclusion criteria

• Subjects with major amputation of the target leg above the ankle joint.
• Planned index limb major amputation above the ankle joint, or any other planned major surgery within 30 days pre- or post-procedure. A planned amputation includ-ing and below the ankle is accepted.
• Recent MI or stroke < 30 days prior to the index procedure.
• Any vascular treatment with any drug-coated devices 4 weeks prior to index procedure
• Known or suspected active infection at the time of the index procedure (abnormal white blood cell count, fever, sepsis or positive blood culture), excluding an infection of a lower extremity wound on the target limb (corresponding to WIfI infection grad 3)
• Subjects with neurotrophic ulcers, heel pressure ulcers or calcaneal ulcers with a risk for major amputation regarding the study leg; Subjects with uncomplicated ulcers can be included.
• Subjects with documented active osteomyelitis of the study leg, excluding the phalanges and metatarsalia, that is beyond cortical involvement of the bone per clinical judgment
• Subjects with systemic vasculitis, such as Lupus Erythematosus or polymyalgia rheumatica on active treatment.
• Subjects receiving systemic corticosteroid therapy (expected dosage > 5 mg of prednisolone or equivalent, per day, during the initial 9 months after procedure) or other systemic immunosuppressant therapy.
• Known allergies or sensitivities to heparin, aspirin (ASA), other anticoagulant/antiplatelet therapies which could not be substituted, and/or sirolimus or an allergy to contrast media that cannot be adequately pre-treated prior to the index procedure.
• The subject is currently enrolled in another investigational device, drug or biological trial.
• Female subjects who are breast feeding at the time of enrollment
• Significant gastrointestinal bleeding or any coagulopathy that would contraindicate the use of anti-platelet therapy
• Prior stent(s) or bypass surgery with safety margin < 3 cm within the target vessel (including stents placed within target vessels during the index procedure prior to randomization).
• Previous procedure with drug-coated balloons in the target vessel within 6 months prior to index procedure.
• Stenosis ≥ 75 % or occlusions (target lesion) located or extending in the popliteal artery or below the ankle joint space. Note: A target lesion can extend into the P3 segment in case it involves a straight lesion extending from the target vessel. Non-significant stenosis below the ankle joint can be allowed in case this is not part of the target lesion.
• Untreated significant (≥ 50 % residual stenosis measured by Duplex Sonography) inflow lesion or occlusion in the ipsilateral iliac, SFA and popliteal arteries.
• Failure to obtain a ≤ 30 % residual stenosis in pre-existing, hemodynamically sig-nificant (≥ 50 % measured by Duplex Sonography) inflow lesions in the ipsilateral iliac, SFA and popliteal artery.
• Aneurysm in the target vessel.
• Angiographic evidence of thrombus within target vessel.
• Pre-dilatation resulted in a major (≥ Grade D) flow-limiting dissection (observed on 2 orthogonal views) or residual stenosis > 50 %.
• Use of alternative therapy, e.g. atherectomy, scoring balloon, laser, radiation therapy, stents as part of target vessel treatment or planned CO2 angiography. Note: Use of stents is only allowed for bailout stenting.