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

Sponsor

University Hospital Inselspital, Berne (Other)

Overall Status

Recruiting

CT.gov ID

NCT04939038

Collaborator

University of Bern (Other), Swiss National Science Foundation (Other)

240

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Diabetic Foot Ulcer	Procedure: Revascularization Procedure: Standard wound care	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 25, 2022

Anticipated Primary Completion Date :

Jan 24, 2026

Anticipated Study Completion Date :

Jan 24, 2026

Arms and Interventions

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: Revascularization Depending on the condition of the patients, patients will have either endovascular or surgical revascularization Procedure: Standard wound care Standard wound care according to guidelines

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: Revascularization

Depending on the condition of the patients, patients will have either endovascular or surgical revascularization

Procedure: Standard wound care

Standard wound care according to guidelines

Outcome Measures

Primary Outcome Measures

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 [90 days after randomization]
i.e. Incomplete epithelization of the index ulcer at 90 days
Number of patients with delayed diabetic foot ulcer healing [45 days after randomization]
Reduction of wound size of less than 50% at 45 days

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Clinic for Angiology, University of Basel	Basel	Switzerland
2	University Clinic for Angiology, University Hospital Inselspital, Berne	Bern	Switzerland	3010
3	Angiologie, Luzerner Kantonsspital	Lucerne	Switzerland
4	Servizio di Radiologia Interventistica, Ospedale Regionale di Lugano	Lugano	Switzerland
5	Clinic for Vascular Surgery, Kantonsspital St. Gallen	Saint Gallen	Switzerland