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

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

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

Study Overview

• Status: Terminated
• Conditions: Diabetic Foot Ulcer
• Intervention / Treatment: Procedure: Standard wound care; Procedure: Revascularization

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland
    • Clinic for Angiology, University of Basel
  • Bern, Switzerland, 3010
    • University Clinic for Angiology, University Hospital Inselspital, Berne
  • Lucerne, Switzerland
    • Angiologie, Luzerner Kantonsspital
  • Saint Gallen, Switzerland
    • Clinic for Vascular Surgery, Kantonsspital St. Gallen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infection of the index ulcer		up to 12 months after randomization
Severity of infection	defined according to Infectious Diseases Society of America (IDSA) classification	up to 12 months after randomization
Index diabetic foot ulcer healing time	days after randomization	up to 12 months after randomization
Change in area of the index ulcer		Compare at baseline and on 45 days, 90 days, 180 days, and 12 months after randomization
Number of patients with major adverse limb events	o Acute limb ischemia (ALI) requiring hospitalization and/ or major repeat revascularization (new bypass graft, jump/interposition graft revision, or thrombectomy / thrombolysis)	up to 12 months after randomization
Number of patients with procedure related serious adverse events		up to 12 months after randomization
Number of patients with major bleeding	as defined by Thrombolysis in Myocardial Infarction (TIMI) Score	up to 12 months after randomization
Number of serious adverse events		up to 12 months after randomization

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Swiss National Science Foundation; University of Bern
• Investigators: Principal Investigator: Prof. Dr. med. Iris Baumgartner, Insel Gruppe AG, University Hospital Bern

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2022
• Primary Completion (Actual): September 18, 2024
• Study Completion (Actual): September 18, 2024

Study Registration Dates

• First Submitted: June 23, 2021
• First Submitted That Met QC Criteria: June 23, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Revascularization; Lower extremity arterial disease; Non-critical peripheral artery disease
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Diabetes Mellitus; Diabetic Angiopathies; Diabetes Complications; Skin Diseases; Skin Ulcer; Leg Ulcer; Diabetic Neuropathies; Foot Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Ulcer; Diabetic Foot; Foot Ulcer; Peripheral Arterial Disease
• Other Study ID Numbers: 1495 DIFU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No