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

Inclusion Criteria:

1. Age ≥ 18 years at the time of consent.
2. Subject has been informed of the nature of the study, is willing to comply with allrequired follow-up evaluations within the defined follow-up visit windows and hassigned an Ethics Committee (EC) approved consent form.
3. Female subjects of childbearing potential have a negative pregnancy test ≤ 7 daysbefore the procedure and are willing to use a reliable method of birth control for theduration of study participation. Female subjects will be exempted from thisrequirement in case they are sterile, infertile, or have been post-menopausal for atleast 12 months (no menses).
4. Life expectancy > 1 year in the investigator's opinion.
5. Subject presenting with documented chronic limb-threatening ischemia (CLTI) in thetarget limb defined as Rutherford category 4, 5 or 6.
6. In case of Rutherford category 5 or 6: Subjects with documented infection grade ≤ 2according to the wound ischemia foot infection (WIfI) classification.
7. All ischemia grades according to the wound ischemia foot infection (WIfI)classifi-cation are allowed.documented infection grade ≤ 2 according to the woundischemia foot infection (WIfI) classification.
8. All ischemia grades according to the wound ischemia foot infection (WIfI) classificationare allowed.
9. Reference Vessel Diameter (RVD) ≥ 2 and ≤ 4.0 mm. 9. ≥ 75 % stenosis or occlusion of thetarget vessel by visual estimate of the treating physician; no minimal lesion lengthrequired.
10. The target lesion may consist of multiple target vessel lesions, if they are ≤ 5 cmaway from each other and if at least one of them is a stenosis ≥ 75 % and all lesions arelocated 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-targetvessels below the knee) and non-target lesions of the target ves-sel can be treated duringthe study index procedure but according to the patient's randomization result (interventional group: Sirolimus-coated balloon or POBA; control group: only POBA).
11. No lesion length limitation, no limitation in number of used devices. 12. The lesionmust be located in the infrapopliteal arteries and above the ankle joint. Lesions may notbe located above the tibioperoneal trunk or below the tibiotalar joint (arteries of thefoot), nor can the treatment (investigational device or standard PTA, includingpre-dilatation) extend beyond these indicated regions for more than 1 cm. Note: A targetlesion can extend into the P3 segment in case it involves a straight uninterrupted lesionextending from the target vessel.
12. Presence of documented run-off to the foot (clearly visible at least one of thefollowing run-off vessels: dorsalis pedis or pedal arch or plantar arteries byangiography). The target vessel should give direct or indirect run-off to the foot.
13. Inflow free from flow-limiting lesion confirmed by angiography. Patients withflow-limiting inflow lesions (≥ 50 % stenosis) can be included if the lesion(s) have beentreated successfully before enrollment, with a maximum residual stenosis of ≤ 30 % pervisual assessment. If an inflow lesion must be treated within or above the P3 segment ofthe 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 notpermitted.
14. Successful pre-dilatation of the (entire) target lesion. Success being documented byangiographic visual estimate of ≤ 50 % residual diameter stenosis of the target lesion andno flow limiting dissection (< Grade D dissection).
15. Participants can only be enrolled once with a single target lesion.

Exclusion criteria:

1. Subjects with major amputation of the target leg above the ankle joint.
2. Planned index limb major amputation above the ankle joint, or any other planned majorsurgery within 30 days pre- or post-procedure. A planned amputation includ-ing andbelow the ankle is accepted.
3. Recent MI or stroke < 30 days prior to the index procedure.
4. Any vascular treatment with PTX or sirolimus-coated devices 60 days prior to indexprocedure
5. Known or suspected active infection at the time of the index procedure (abnormal whiteblood cell count, fever, sepsis or positive blood culture), excluding an infection ofa lower extremity wound on the target limb (corresponding to WIfI infection grad 3)
6. Subjects with neurotrophic ulcers, heel pressure ulcers or calcaneal ulcers with arisk for major amputation regarding the study leg; Subjects with uncomplicated ulcerscan be included.
7. Subjects with documented active osteomyelitis of the study leg, excluding thephalanges and metatarsalia, that is beyond cortical involvement of the bone perclinical judgment
8. Subjects with systemic vasculitis, such as Lupus Erythematosus or polymyalgiarheumatica on active treatment.
9. Subjects receiving systemic corticosteroid therapy (expected dosage > 5 mg ofprednisolone or equivalent, per day, during the initial 9 months after procedure) orother systemic immunosuppressant therapy.
10. Known allergies or sensitivities to heparin, aspirin (ASA), otheranticoagulant/antiplatelet therapies which could not be substituted, and/or sirolimusor an allergy to contrast media that cannot be adequately pre-treated prior to theindex procedure.
11. The subject is currently enrolled in another investigational device, drug orbiological trial.
12. Female subjects who are breast feeding at the time of enrollment
13. Significant gastrointestinal bleeding or any coagulopathy that would contraindicatethe use of anti-platelet therapy
14. 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 torandomization).
15. Previous procedure with drug-coated balloons in the target vessel within 6 monthsprior to index procedure.
16. Stenosis ≥ 75 % or occlusions (target lesion) located or extending in the poplitealartery or below the ankle joint space. Note: A target lesion can extend into the P3segment 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 partof the target lesion.
17. Untreated significant (≥ 50 % residual stenosis measured by Duplex Sonography) inflowlesion or occlusion in the ipsilateral iliac, SFA and popliteal arteries.
18. Failure to obtain a ≤ 30 % residual stenosis in pre-existing, hemodynamicallysig-nificant (≥ 50 % measured by Duplex Sonography) inflow lesions in the ipsilateraliliac, SFA and popliteal artery.
19. Aneurysm in the target vessel.
20. Angiographic evidence of thrombus within target vessel.
21. Pre-dilatation resulted in a major (≥ Grade D) flow-limiting dissection (observed on 2orthogonal views) or residual stenosis > 50 %.
22. Use of alternative therapy, e.g. atherectomy, scoring balloon, laser, radiationtherapy, stents as part of target vessel treatment. Note: Use of stents is onlyallowed for bailout stenting.