LIMES: 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

Sponsor

Jena University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04772300

Collaborator

Concept Medical Inc. (Industry), VascuScience GmbH (Other), CoreLab Black Forest (Other), Center for Clinical Studies, University Hospital Jena (Other)

230

Enrollment

Locations

Arms

64.6

Anticipated Duration (Months)

12.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a prospective, interventional, multicenter 1:1 randomized trial.

The trial evaluates the safety and efficacy of the Magic Touch PTA sirolimus drug-coated balloon in comparison to the treatment with POBA (control device) in patients with infrapopliteal artery disease.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Artery Disease	Combination Product: Percutaneous Transluminal Angioplasty (PTA) MagicTouch Sirolimus Coated PTA Balloon Catheter Device: Percutaneous Transluminal Angioplasty (PTA) with non-coated balloon catheter (POBA)	N/A

Detailed Description

The primary 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 noninferior to Plain Old Balloon Angioplasty (POBA) regarding treatment of occlusions in the infrapopliteal arteries (located below the P3 segment of the popliteal artery to the tibiotalar joint) in patients pre-senting with chronic limb-threatening ischemia (CLTI) (Rutherford 4-6).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

230 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

1:1-randomization, parallel design, stratified by center.1:1-randomization, parallel design, stratified by center.

Masking:

Double (Participant, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Prospective Multi-Center Randomized Controlled Trial to Evaluate the Safety and Efficacy of SiroLIMus Drug Coated Balloon Versus Non-coated Standard Angioplasty for the Treatment of Infrapopliteal Occlusions in Patients With PEripheral Arterial DiSease

Actual Study Start Date :

Feb 10, 2022

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Jul 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus DCB group Intervention with Sirolimus-coated balloon catheter	Combination Product: Percutaneous Transluminal Angioplasty (PTA) MagicTouch Sirolimus Coated PTA Balloon Catheter PTA with an sirolimus drug-coated balloon catheter (SRL-DCB) in the infrapopliteal artery
Active Comparator: POBA group Intervention with non-coated balloon catheter (POBA)	Device: Percutaneous Transluminal Angioplasty (PTA) with non-coated balloon catheter (POBA) PTA with an non-coated balloon catheter (POBA) in the infrapopliteal artery

Arm

Intervention/Treatment

Experimental: Sirolimus DCB group

Intervention with Sirolimus-coated balloon catheter

Combination Product: Percutaneous Transluminal Angioplasty (PTA) MagicTouch Sirolimus Coated PTA Balloon Catheter

PTA with an sirolimus drug-coated balloon catheter (SRL-DCB) in the infrapopliteal artery

Active Comparator: POBA group

Intervention with non-coated balloon catheter (POBA)

Device: Percutaneous Transluminal Angioplasty (PTA) with non-coated balloon catheter (POBA)

PTA with an non-coated balloon catheter (POBA) in the infrapopliteal artery

Outcome Measures

Primary Outcome Measures

composite of limb salvage and primary patency at 6 months [6 months after study procedure (PTA with medical product under investigation or comparator)]
composite of limb salvage and primary patency at 6 months. Patency is defined as the absence of target lesion occlusion (no flow) as determined by duplex ultrasound and/or absence of clinically-driven TLR revascularization (CD-TLR), where clinically-driven is defined as a restenosis of ≥ 70 % in the target lesion with Wound persistence and/or Increase in size of pre-existing wounds and/or Occurrence of new wounds and/or Deterioration of Rutherford Class

Secondary Outcome Measures

MALE-POD [1 month after study procedure.]
Major Adverse Limb Events (MALE) with perioperative death (POD) after 1 month. Major Adverse Limb Events (MALE) are defined as above-ankle amputation or major reintervention (i.e., new bypass graft, interposition graft revision, or thrombectomy/thrombolysis) of the treated limb involving a BTK artery. Perioperative death (POD) is defined as death within 30 days after index procedure.
rate of clinically-driven TVR [1, 6, 12, 24 and 36 months after study procedure.]
occurrence of clinically-driven TVR at certain time points
TVR rate in treated target vessel and non-target vessels [1, 6, 12, 24 and 36 months after study procedure.]
Rate of all TVR including treated non-target vessel at 1, 6, 12, 24 and 36 months.
TVR rate [1, 6, 12, 24 and 36 months after study procedure.]
Rate of all TVR at 1, 6, 12, 24 and 36 months.
Primary Patency rate [1, 6, 24 and 36 months after study procedure.]
Primary Patency rate at certain time points
Primary Patency of target and treat non-target vessel [1, 6, 24 and 36 months after study procedure.]
Primary Patency rate of target and treat non-target vessel at certain time points
Secondary Patency rate [1, 6, 24 and 36 months after study procedure.]
Secondary Patency rate at certain time points
Secondary Patency of target and treat non-target vessel [1, 6, 24 and 36 months after study procedure.]
Secondary Patency rate of target and treat non-target vessel at certain time points
Re-occlusion rate [1, 6, 12, 24 and 36 months after study procedure.]
Rate of re-occlusion at certain time points, defined as the absence of flow in the target vessel as determined by duplex ultrasound
Number of treated Non-target vessels [36 months after study procedure]
Number of treated Non-target vessels
Walking Capacity Assessment 1 [1, 6, 12, 24 and 36 months after study procedure.]
patient-self-assessment of walking distance at certain time points
Walking Capacity Assessment 2 [1, 6, 12, 24 and 36 months after study procedure.]
VascuQoL questionnaire (Vascular Quality of Life Questionnaire) at certain time points; 25 questions (scale 1 to 7); best score 175, worst score 25.
Target Limb Major Amputations [1, 6, 12, 24 and 36 months after study procedure.]
Rate of target limb major amputations at certain time points
all-cause mortality [1, 6, 12, 24 and 36 months after study procedure.]
Rate of all-cause death at certain time points
Amputation free survival (AFS) [1, 6, 12, 24 and 36 months after study procedure.]
Amputation free survival (AFS) at certain time points
Amputation free survival and resolved CLTI [1, 6, 12, 24 and 36 months after study procedure.]
Amputation free survival and resolved CLTI at certain time points
Ankle-Brachial-Index (ABI) [1, 6, 12, 24 and 36 months after study procedure.]
Change in ankle-brachial index (ABI) from pre-procedure to certain time points
Toe-Brachial-Index (TBI) [1, 6, 12, 24 and 36 months after study procedure.]
Change in toe-brachial index (TBI) from pre-procedure to certain time points
Rutherford classification [1, 6, 12, 24 and 36 months after study procedure.]
Change in Rutherford category from pre-procedure to certain time points
Primary sustained clinical improvement [1, 6, 12, 24 and 36 months after study procedure.]
improvement shift in the Rutherford Category of one class or more in amputation free surviving patients without the need for clinically driven TVR at certain time points
Secondary sustained clinical improvement [1, 6, 12, 24 and 36 months after study procedure.]
improvement shift in the Rutherford classification of one class or more in amputation free surviving patients including those with clinically driven TVR at certain time points
EQ-5D-3L [1, 6, 12, 24 and 36 months after study procedure.]
Change in EQ-5D-3L (Quality of Life questionnaire) from pre-procedure to certain time points; 5 questions (scale 1 to 3), best score 5, worst score 15.
Wound healing [1, 6, 12, 24 and 36 months after study procedure.]
Rate of wound healing from pre-procedure to certain time points
New or recurrent wound of the target limb [1, 6, 12, 24 and 36 months after study procedure.]
New or recurrent wound of the target limb from pre-procedure to certain time points
Change in VascuQoL [1, 6, 12, 24 and 36 months after study procedure.]
Walking capacity assessment by VascuQoL from pre-procedure to certain time points. 25 questions (scale 1 to 7); best score 175, worst score 25.
Length of in-hospital-stay [1, 6, 12, 24 and 36 months after study procedure.]
Days of hospitalization at certain time points
Major Adverse Limb Events (MALE) [1, 6, 12, 24 and 36 months after study procedure.]
MALE at certain time points
Device Success [at index procedure]
Device Success defined as exact deployment of the device according to the instructions for use
Technical Success [at index procedure]
Technical Success defined as successful vascular access and completion of the endovascular procedure and immediate morphological success with ≤ 50 % residual diameter reduction of the treated lesion on completion angiography
Procedural success [at index procedure]
Procedural success, defined as combination of technical success, device success and absence of procedural complications
composite endpoint: patency, rate of overall-cause death and amputation-free survival [1, 6, 12, 24 and 36 months after study procedure.]
composite endpoint consisting of patency, rate of overall-cause death and amputation-free survival at certain time points
composite endpoint: rate of all-cause death, target limb major amputation and clinically-driven TLR [1, 6, 12, 24 and 36 months after study procedure.]
composite endpoint consisting of rate of all-cause death, target limb major amputation and clinically-driven Target Lesion Revascularization at certain time points

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 0-2 and/or ischemia grade 2-3 according to the wound ischemia foot infection (WIfI) classification.
Reference Vessel Diameter (RVD) ≥ 2 and ≤ 4.0 mm.
Total occlusion (100 % stenosis) of the target vessel; 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 occluded 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) 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).
No lesion length limitation, no limitation in number of used devices.
The lesion must be located in the infrapopliteal arteries and above the ankle joint. Lesions may not extend above the tibioperoneal trunk (P3 segment of the popliteal artery) 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. Non-significant stenosis below the ankle joint can be allowed in case this is not part of the target lesion and does not require treatment.
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.
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). TL is not considered non-dilatable by the operator due to concentric, circumferential calcium and TL can be treated successfully by balloon angioplasty without the need for bail-out stenting.

Exclusion Criteria:

Subjects with amputation of the target leg above the metatarsal level.
Planned index limb amputation above the metatarsal level, or any other planned major surgery within 30 days pre- or post-procedure. A planned amputation including and below the metatarsal level (1 or multiple rays) is accepted.
Recent MI or stroke < 30 days prior to the 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 (only WIfI infection grade 0-2 allowed).
Subjects with infection grade 3 and ischemia grade 0 and/or 1 according to WIfI classification.
Subjects with neurotrophic ulcers, heel pressure ulcers or calcaneal ulcers with a risk for major amputation; Subjects with uncomplicated ulcers can be included.
Subjects with documented active osteomyelitis, excluding the phalanges, that is beyond cortical involvement of the bone per clinical judgment.
Subjects with vasculitis, systemic 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).
Known allergies or sensitivities to heparin, aspirin (ASA), other anticoagulant/anti-platelet 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 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.
Occlusions 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 and does not require treatment.
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 significant (≥ 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. Note: Use of stents is only allowed for bailout stenting.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	AKH Wien, Universitätsklinik für Innere Medizin II, Klinische Abteilung für Angiologie	Wien	Austria	1090
2	Allgemeines Krankenhaus der Stadt Wien (Wien AKH), Department of Radiology	Wien	Austria	1090
3	Hanusch-Krankenhaus	Wien	Austria	1140
4	Universitäts-Herzzentrum Freiburg-Bad Krozingen; Clinic for Cardiology and Angiology II	Bad Krozingen	Germany	79189
5	Fürst-Stirum-Klinik Bruchsal, Klinik für Kardiologie, Angiologie, Diabetologie, Neurologie und Intensivmedizin	Bruchsal	Germany	76646
6	DIAKO gGmbH, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie	Flensburg	Germany	24939
7	Universitätsklinikum Heidelberg, Medizinische Klinik III, Kardiologie, Angiologie und Pneumologie	Heidelberg	Germany	69120
8	University Hospital Jena	Jena	Germany	07747
9	University Hospital Leipzig	Leipzig	Germany	04103
10	Marienhaus Klinikum Mainz, Klinik für Diagnostische und Interventionelle Radiologie	Mainz	Germany	55131
11	Gefäßpraxis im Tal	München	Germany	80331
12	St. Franziskus-Hospital GmbH, Klinik für Gefäßchirurgie	Münster	Germany	48145
13	Universitätsklinikum Münster, Klinik für Kardiologie I, Koronare Herzkrankheit, Herzinsuffizienz und Angiologie	Münster	Germany	48149
14	Elblandklinikum Radebeul, Gefäßzentrum	Radebeul	Germany	01445
15	Krankenhaus Barmherzige Brüder Regensburg, Institut für Radiologie, Neuroradiologie und Nuklearmedizi	Regensburg	Germany	93049
16	Imland Klinik Rendsburg, Institut für Diagnostische und Interventionelle Radiologie/Neuroradiologie	Rendsburg	Germany	24768
17	Elblandklinikum Riesa, Gefäßzentrum	Riesa	Germany	01589
18	RoMed Klinikum Rosenheim, Diagnostische und Interventionelle Radiologie	Rosenheim	Germany	83022
19	MEDINOS-Kliniken Sonneberg, Gefäßzentrum	Sonneberg	Germany	96515