Efficacy and Safety of Cold Atmospheric Plasma Combined With Endovascular Intervention in Patients With Diabetic Foot Ulcers and Lower Extremity Arterial Occlusion: a Randomized, Double-blind, Placebo-controlled Clinical Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Change in ulcer area between groups
研究概览
简要总结
Critical limb ischemia is the end-stage manifestation of peripheral arterial disease (PAD), frequently presenting as ischemic rest pain, ulceration, or gangrene. Diabetes mellitus is a major risk factor for lower extremity arterial occlusion, with infrapopliteal arteries most commonly affected. Patients with diabetic foot ulcers (DFUs) have a high prevalence of neurovascular complications, poor healing, and elevated amputation and mortality rates. Large-scale cohort studies indicate that five-year survival after amputation in this population is only about 50%, underscoring the need for more effective therapies.
Endovascular revascularization has become the first-line treatment for diabetic lower limb ischemia. However, despite successful revascularization, persistent microvascular dysfunction and difficult-to-heal ulcers remain common due to chronic inflammation, impaired angiogenesis, and tissue repair deficits. Current advanced wound dressings provide limited benefit and are often costly.
Cold atmospheric plasma (CAP) has emerged as a promising adjunctive therapy, with demonstrated antimicrobial activity-including efficacy against multidrug-resistant organisms-and the ability to promote microcirculation and wound healing. CAP generates reactive oxygen and nitrogen species that disrupt bacterial membranes and may also stimulate tissue regeneration. Preclinical and clinical studies suggest that CAP can accelerate healing in chronic wounds and is well tolerated by patients.
Given these advantages, the present study aims to assess the efficacy and safety of CAP combined with endovascular intervention in patients with diabetic foot ulcers and lower extremity arterial occlusion, to inform future clinical application of this novel technology.
详细描述
End-stage peripheral arterial disease (PAD) is characterized by critical limb ischemia, which manifests clinically as insufficient arterial perfusion leading to ischemic rest pain, ulceration, and gangrene. A substantial proportion of these cases occur in patients with diabetes complicated by lower extremity arterial occlusion. Ischemia in diabetic patients predominantly affects infrapopliteal arteries, often presenting bilaterally and symmetrically, with diffuse lesions that commonly involve the entire vessel wall. These patients are more prone to both intimal atherosclerosis and medial arterial calcification.
A large multicenter cohort study in China that enrolled 669 patients with diabetic foot ulcers from 15 tertiary hospitals reported that more than 98% had underlying neurovascular pathology. The overall amputation rate was 19.03%, with major and minor amputation rates of 2.14% and 16.88%, respectively. Notably, the five-year survival rate after amputation was approximately 50%, which is lower than that observed for many malignancies. According to a large European cohort study, about half of diabetic foot ulcers are attributable to neuropathic or ischemic etiologies. Both macrovascular and microvascular dysfunctions jointly impair tissue perfusion and exacerbate diabetic foot pathology. From a clinical perspective, successful arterial revascularization alone is not sufficient; maintenance and optimization of distal microcirculatory perfusion following revascularization are also essential for effective ulcer healing.
With advances in endovascular techniques, infrapopliteal angioplasty has become the first-line treatment for diabetic lower limb ischemia, with proven efficacy. However, even after successful revascularization, some patients continue to suffer from inadequate distal perfusion due to microembolization or from persistent, hard-to-heal ulcers driven by the underlying pathophysiology of diabetic wounds. Several studies have demonstrated that diabetic patients experience metabolic dysregulation, local wound hyperglycemia, and accumulation of advanced glycation end-products (AGEs); combined with immune dysfunction and chronic inflammation, these factors maintain wounds in a persistent inflammatory state. Chronic inflammation suppresses vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) expression, impairs endothelial cell function, and leads to angiogenesis disorders and delayed tissue repair. Reduced VEGF and ANG-1 expression has been confirmed in skin specimens from diabetic patients. In addition, peripheral neuropathy further inhibits neovascularization.
Despite widespread clinical use of advanced wound dressings-such as hydrogels, natural or synthetic polymer-based products, and other dressings designed specifically for diabetic ulcers-treatment efficacy remains limited, and costs can be substantial. For patients with diabetic foot ulcers complicated by large-vessel occlusion, ongoing assessment and support of distal microvascular perfusion remain a major unmet clinical need, even after successful revascularization.
Cold atmospheric plasma (CAP) has been widely adopted in medical applications and has demonstrated robust antimicrobial activity as well as the capacity to enhance tissue microcirculation and promote wound healing, with excellent patient tolerance. Multiple preclinical and clinical studies have confirmed the bactericidal efficacy of CAP, including activity against multidrug-resistant organisms. For example, Brun et al. reported that CAP effectively eradicates Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) in vitro, achieving results comparable to antibiotics but with higher efficiency. Lis et al. found that CAP could also inactivate MRSA, Klebsiella pneumoniae, and Acinetobacter baumannii. Korean researchers Kim et al. demonstrated that CAP effectively disrupts biofilms formed by P. aeruginosa and other pathogens in canine skin and ear infections. In a prospective clinical study, Stratmann et al. showed that CAP treatment accelerates wound healing in diabetic foot ulcers. Boekema et al. [6] reported a significant reduction in bacterial load and no serious adverse events in patients with P. aeruginosa infections treated with CAP, confirming its safety profile.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
Participants in the placebo group will undergo a sham procedure, in which the electric field required for plasma generation will be disabled, so that no plasma is produced. Only the operating sounds of the device will be simulated, ensuring blinding for both participants and clinical staff.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 18-80 years, with a diagnosis of type 1 or type 2 diabetes and diabetic foot ulcer; glycated hemoglobin (HbA1c) ≤ 10%.
- •Presence of at least one chronic foot ulcer persisting for at least three weeks, with no signs of healing after standard-of-care treatment based on current clinical guidelines. The ulcer must be classified as Wagner-Armstrong grade 1D or 2D (Wagner: superficial ulcer [grade 1] or ulcer extending to tendon [grade 2]; Armstrong: presence of both ischaemia and infection [stage D]).
- •Documented infrapopliteal arterial stenosis or occlusion by vascular ultrasound and/or CT angiography (CTA), meeting indications for revascularization. All enrolled patients must have received successful infrapopliteal balloon angioplasty, with intraoperative angiography confirming target artery patency.
- •Provision of written informed consent.
排除标准
- •Concurrent treatment of the wound with local vacuum therapy or maggot therapy.
- •Undergoing dialysis.
- •Use of local active antibiotics.
- •Treatment with platelet-rich fibrin.
- •Women of childbearing potential without effective contraception, or women who are actively breastfeeding.
- •Presence of other severe organ dysfunction, with an expected survival of less than six months.
- •Participation in another clinical trial within the past three months or currently enrolled in another clinical trial.
研究组 & 干预措施
CAP therapy
干预措施: Cold atmospheric plasma (CAP) (Device)
CAP therapy
干预措施: Successful infrapopliteal angioplasty (Other)
the placebo group
干预措施: Sham Procedure (Device)
the placebo group
干预措施: Successful infrapopliteal angioplasty (Other)
结局指标
主要结局
Change in ulcer area between groups
时间窗: From Baseline (Day 0) to Day 21 post-randomization
The ulcer area (cm²) will be measured daily during the first five days, and every other day for the subsequent eight visits (13 follow-up assessments in total)
次要结局
- Time to 10% reduction in ulcer area(From Baseline (Day 0) to Day 21 post-randomization)
- Time to 20% reduction in ulcer area(From Baseline (Day 0) to Day 21 post-randomization)
- Time to onset of clinical signs of infection(From Baseline (Day 0) to Day 21 post-randomization)
- Change in pain score(From Baseline (Day 0) to Day 21 post-randomization)
- Change in quality of life (EQ-5D questionnaire)(Baseline (Day 0) and Day 21 post-randomization)
- Change in quality of life (SF-12 questionnaire)(Baseline (Day 0) and Day 21 post-randomization)
- Incidence of local skin irritation(From Baseline (Day 0) to Day 21 post-randomization)
- Incidence of local bleeding(From Baseline (Day 0) to Day 21 post-randomization)
- Incidence of local burning sensation(From Baseline (Day 0) to Day 21 post-randomization)
研究者
Lin Tao
Associate Professor
Shenyang Medical College