Timing of Revascularization in Patients With Diabetic Foot Ulcer and Non-critical Peripheral Artery Disease

Study Overview
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Brief Summary
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This study investigates whether, compared to standard treatment, immediate restoration of blood flow (revascularization) can reduce complications and improve diabetic foot ulcer healing.

Detailed Description
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Background: In approximately 80% of diabetes-related lower extremity amputations, patients suffer from a foot ulcer, often caused by lower extremity arterial disease. Due to lower extremity arterial disease (LEAD), diabetic patients with foot ulcers often require lower limb amputation. Achieving arterial supply (revascularization) to the ulcer is the most important factor in healing the diabetic foot ulcer and reduces the risk of amputation. The current standard of care recommends revascularization after six weeks in patients with low-grade arterial disease of the lower extremities and nonhealing foot ulcer. The aim of this study is to demonstrate that in patients with low grade arterial disease of the lower extremities and diabetic foot ulcers, immediate revascularization results in fewer cardiovascular problems and amputations, as well as improved ulcer healing, compared to the current standard of care. Study procedure: After inclusion in the study, participants will be randomized into the control arm or the active arm. In the control arm standard wound care will be performed. In the active arm, revascularization will be performed on top of standard wound care within 7 days after randomization. Post-revascularization analysis on ankle- and toe pressure, laboratory analysis, and wound care team assessment and therapy will be performed 24 h post operation. Follow up will be on 45, 90, 180 and 365 day for patients of both arms, where ankle- and toe pressure, laboratory analysis, and wound care team assessment and therapy will be performed. Number of Participants: 240 participants in total, 120 per treatment arm Study duration: 4 years Study Centre(s): International multi-centre study with approximately 8-12 centres Participating countries: Switzerland, Germany

Official Title
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Timing of Revascularization in Patients With Diabetic Foot Ulcer and Non-critical Peripheral Artery Disease: a Randomized, Controlled Trial

Conditions
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Diabetic Foot Ulcer

Intervention / Treatment
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* Procedure: Revascularization
* Procedure: Standard wound care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent as documented by signature Patients that are at least 18 years old Patients that have at least one DFU(s) of ≥ 0.2 cm2 and ≤ 10 cm2 as assessed by the ruler method multiplying the greatest length and width of the ulcer after debridement to determine the surface area. The largest eligible ulcer (≤ 10 cm2) will be defined as index ulcer and the corresponding extremity as index limb (in case of multiple equally sized ulcers the following rules will apply: If on different feet, the dominant side and if on the same foot, the more peripheral one will be the index ulcer) Patients that have non-critical LEAD of the index leg, defined by a single non-invasive examination at screening: Ankle brachial index (ABI) ≥ 0.5 and ≤ 0.9 AND absolute ankle pressure ≥ 50 mmHg OR ABI > 0.9 OR incompressible ankle pressures AND toe brachial index (TBI) ≤ 0.7 AND absolute toe pressure ≥ 30 mmHg Patients on medical treatment for glycemic control with diagnosis of diabetes mellitus that was assessed by criteria as recommended by the guideline 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Or patient without medical treatment but diagnosed with diabetes mellitus via HbA1c. Patients with life expectancy > 12 months and without any disabilities due to end-stage cancer, heart failure, severe chronic obstructive pulmonary disease (COPD), or dementia Exclusion Criteria: Critical limb ischemia of the index leg defined as ABI ≤ 0.4 (or absolute ankle pressure < 50 mmHg) No option to assess for toe pressure due to any reason at baseline if ABI > 0.9 or incompressible ankle pressures and patient inclusion is based on the toe pressure criteria. Need for major amputation Severe infection at the index foot according to IDSA classification Patient refuses minor amputation despite strong recommendation due to severe infection, necrosis or osteomyelitis at screening assessment Any revascularization procedure at the index leg within 3 months before randomization Positive urine or blood pregnancy test result, breast feeding or intention to become pregnant Non-compliance for any reason to procedures or study assessments (e.g. due to cognitive impairment or geographic distance) Participation in another drug study within the 30 days preceding or during the present study Untreated known antiphospholipid antibody syndrome and polycythaemia vera Known significant bleeding risk, or known coagulation disorder (INR > 3.0 and platelet count < 30,000/mm3) without any option to correct within 7 calendar days after initial wound assessment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>Standard wound care for diabetic wound ulcer | Procedure: Standard wound care<br>* Standard wound care according to guidelines<br>|
| Experimental: Immediate revascularization<br>Patient will have revascularization 0 - 7 days after initial wound assessment and then receive standard wound care for diabetic wound ulcer | Procedure: Revascularization<br>* Depending on the condition of the patients, patients will have either endovascular or surgical revascularization<br>Procedure: Standard wound care<br>* Standard wound care according to guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with cardiovascular death |  | up to 12 months | 
| Number of patients with non-fatal myocardial infarction or all-cause stroke |  | up to 12 months after randomization | 
| Number of patients with major amputation |  | up to 12 months after randomization | 
| Number of patients with Minor amputation |  | up to 12 months after randomization | 
| Number of patients with missed diabetic foot ulcer healing | i.e. Incomplete epithelization of the index ulcer at 90 days | 90 days after randomization | 
| Number of patients with delayed diabetic foot ulcer healing | Reduction of wound size of less than 50% at 45 days | 45 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with new ulcer of the index foot |  | up to 12 months after randomization | 
| Number of patients with all clinically-driven revascularizations at the index limb | excluding primary revascularization in the immediate re-vascularization group | up to 12 months after randomization | 
| Each component of the primary outcome individually | Primary outcome 1 to 6 | up to 12 months after randomization | 
| Number of in-hospital days and costs | (based on Disease-Related Group codes) as a measure of health service utilization | up to 12 months after randomization | 
| Change in quality of life (QoL) assessed by the Cardiff Wound Impact Schedule questionnaire | Scores are transformed onto a scale of 0 - 100, a high score represents a 'good' QoL and a low score represent a 'poor' QoL | from baseline to 90 days and 12 months after randomization | 
| Number of patients with major amputation-free survival | death of any cause or major amputation | up to 12 months after randomization | 
| Number of patients with all-cause death |  | up to 12 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Revascularization, Lower extremity arterial disease, Non-critical peripheral artery disease