Study of the R3 Vascular Drug-Eluting Bioresorbable Scaffold in Treating Below the Knee Arterial Disease

Overview

This first-in-human clinical feasibility study will evaluate the safety and performance of the R3 Vascular MAGNITUDE® Bioresorbable Drug-Eluting Scaffold and Delivery System in patients undergoing treatment for peripheral arterial disease severe enough to have significantly reduced the blood supply to their leg. The severe reduction in blood flow causes lifestyle limiting leg pain for these patients, and may lead to amputation of the affected limb due to the loss of tissue in the leg or foot from ulcers or gangrene. The investigational device being studied in this trial is intended to restore blood flow to the affected limb, providing symptomatic relief to the patient and reducing the risk of limb amputation. The scaffold is a type of vascular stent placed within the diseased artery below the knee to improve blood flow. Unlike commercially available metallic stents which are permanently placed within the artery, the MAGNITUDE® Bioresorbable scaffold is made of a polymer material that will completely dissolve away over time, providing the support necessary to the artery while it is healing after the treatment procedure and then slowly disappearing from the artery once that support is no longer needed. The investigational scaffold has been successfully used to treat vascular blockages in the coronary arteries of the heart, but the RESOLV I study will be the first time this device has been used to improve blood flow in the arteries of the lower leg. Patients enrolled in this study may have up to three vascular blockages in their lower leg arteries treated with the MAGNITUDE® Bioresorbable scaffold, and then will be assessed over the course of the following five years to evaluate whether the investigational treatment was successful in safely alleviating their leg pain and other symptoms.

The prevalence of peripheral artery disease (PAD) is estimated to be over 200 million. Critical limb ischemia (CLI) is considered the most advanced stage of PAD, occurring in about 10% of PAD patients. CLI patients typically present with ischemic rest pain, nonhealing ulcerations, infection, and/or gangrene. It is associated with a high risk of major amputation (lower limb amputations in 10% - 40% of patients at 6 months), cardiovascular events, and death (mortality rate of 20% within 6 months after the diagnosis and 50% at 5 years). A large percentage of CLI patients have occlusive disease in the infrapopliteal artery, especially in diabetics where PAD is 3 - 4 times more common. CLI related to diabetes is often more extensive, with multiple long segmental occlusions resulting in a 5 - 30-fold increase in the rate of amputations. Surgical and catheter-based revascularization procedures are typically performed to restore distal perfusion and prevent amputation in symptomatic patients. Surgical bypass has been shown to be an effective treatment when anatomic and patient risk factors permit this approach. However, patients with CLI are often poor surgical candidates because of the absence of suitable graft vessels or the presence of significant medical comorbidities. During the past decade, therapies such as percutaneous transluminal angioplasty (PTA) and percutaneous treatment with balloons or the off-label use of coronary stents that deliver antiproliferative drugs directly to the vessel wall to inhibit neointimal hyperplasia have been on the rise and have decreased the rates of open bypass surgery. Percutaneous transluminal angioplasty has become the first line revascularization therapy for patients with symptomatic peripheral artery disease. Published literature indicates that while uncoated balloon angioplasty has a high rate of technical success in obtaining a patent lumen, restenosis requiring repeat revascularization or amputation is common. For femoropopliteal (above the knee) disease, percutaneous treatment with a balloon that delivers an antiproliferative agent (usually paclitaxel) directly to the vessel wall inhibits neointimal hyperplasia and significantly reduces the rate of target lesion revascularization and restenosis, while maintaining a safety profile comparable to that of uncoated balloons. On the other hand, drug-coated balloon (DCB) therapy in the infrapopliteal (below the knee) arteries has not shown similarly convincing evidence of superiority over PTA, and in general, the use of DCB below the knee remains controversial. Metallic drug-eluting stents have been shown to effective in reducing both abrupt vessel closure and restenosis rates in the management of peripheral vascular disease. However, metallic implants also negatively impact the vessel wall by permanently preventing vasomotion, autoregulation, and adaptive remodeling. In addition, there is a risk of late vessel failure due to incomplete endothelialization of the implant, stent fracture, or malapposition. Metallic implants may also cause artifacts with noninvasive imaging and complicate future revascularization procedures. Bioresorbable scaffolds provide similar mechanical properties to metallic stents during the blood vessel remodeling phase following angioplasty, while also delivering an antiproliferative drug to the site of vascular injury to minimize neointimal hyperplasia. However, once these tasks are complete, the scaffold begins a reabsorption process and eventually disappears entirely from the vessel, leaving the native artery free of any implant. For these reasons, bioresorbable scaffolds may offer a new standard for restorative therapy in the peripheral vasculature. This first-in-human clinical feasibility study of the R3 Vascular MAGNITUDE® scaffold will evaluate the safety and performance of a bioresorbable scaffold with a thin strut design (98 µm wall thickness) and a coating of the antiproliferative drug Sirolimus for treating patients with lifestyle limiting claudication or chronic limb threatening ischemia. The objective is to perform an initial evaluation of the investigational device in a patient population undergoing percutaneous transluminal intervention with stenting for the treatment of infrapopliteal artery lesions. The thin strut design of the MAGNITUDE® scaffold offers improved deliverability and the potential for higher vessel patency rates compared to other thicker strut bioresorbable scaffolds currently under investigation for this particular indication. In addition, compared with metallic stents, the R3 Vascular bioresorbable scaffold provides sustained support to the vessel wall following revascularization while vascular healing occurs, after which the scaffold predictably degrades leaving no permanent implant behind. The MAGNITUDE® scaffold has been shown to be biocompatible, maintain mechanical integrity over time, and provide controlled drug release through extensive validations in pre-clinical testing and clinical studies enrolling approximately 200 patients being treated for coronary artery disease. The RESOLV I clinical investigation is a prospective, single-arm, multi-center first-in-human feasibility study of the R3 Vascular MAGNITUDE® Bioresorbable Drug-Eluting Scaffold and Delivery System for treating vascular disease in the infrapopliteal arteries. It will enroll a maximum of 30 patients from up to 9 investigational centers in Italy, Austria, and Canada. Eligible patients who are at least 18 years of age with lifestyle limiting claudication or chronic limb threatening ischemia (Rutherford-Becker categories 3 - 5) that elect to undergo revascularization with stenting of up to three different de novo or restenotic infrapopliteal artery lesions will be treated with the investigational device and followed for five years post-implantation. Safety of the investigational scaffold will be assessed at 6 months as the composite rate of Major Adverse Limb Events (above ankle amputation in the index limb or major re-intervention) and peri-operative (30-day) mortality. Performance of the device will be evaluated as the primary patency rate of the treated vessels at 6 months, assessed by angiography. Multiple other angiographic, duplex ultrasound, and clinical assessments will be performed during the 5-year follow-up period. It is expected that the subjects enrolled in this study will experience the same benefits as patients treated with the currently available coronary (used off label in the peripheral arteries) drug-eluting metallic stents. Treatment with the investigational scaffold may provide physicians with a promising alternative to permanent stenting, which has been shown to interfere with future treatments such as PTA or surgery. Additionally, since the investigational scaffold is designed to provide mechanical support to the target lesion for the required healing period post-treatment and disappear once healing is complete, this may allow for positive remodeling of the artery and reduce the risk of late complications (i.e., endothelial cell proliferation, restenosis, thrombosis, etc.).