Does Increasing Oxygen Nurture Your Symptomatic Ischemic Ulcer Sufficiently?

Study Overview
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Brief Summary
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The goal of this multicenter, multi-national, multi-arm, multi-stage, randomized controlled trial, is to determine the added benefit of hyperbaric oxygen treatment (HBOT) in patients with diabetic foot ulcers and peripheral vascular disease. The main question is: - What is the difference is the major amputation rate between the study arms? Participants will be randomized to 20, 30 or 40 sessions of HBOT or a control group.

Detailed Description
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Objective: The primary objective is to assess the (cost-) effectiveness of HBOT in addition to standard wound care and vascular surgical treatment for patients with a DFU and leg ischaemia. Study design: An international, multi-arm multi-stage (MAMS) design is chosen to conduct an efficient randomised clinical trial. At a planned interim analysis the best performing study arm(s) will be chosen to continue. Study population: We need up to 544 patients with a Meggitt-Wagner stage 3 or 4 DFU and proven peripheral ischaemia. Intervention: Patients will be randomised to receive standard care (wound treatment and surgical interventions following international guidelines) with either 0, 20, 30 or at least 40 sessions of HBOT. These sessions will compromise 90-120 minutes of HBOT at a pressure of 2.2-2.5 ATA according to international standards. Main study parameters/endpoints: The primary endpoint is major amputation rate after 12 months. Secondary objectives are amputation-free survival, wound healing, health-related quality of life and cost-effectiveness of the interventions.

Official Title
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Does Increasing Oxygen Nurture Your Symptomatic Ischemic Ulcer Sufficiently?

Conditions
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Peripheral Vascular Disease, Diabetic Foot Ulcer, Amputation

Intervention / Treatment
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* Drug: Hyperbaric oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type I or II diabetes One or more deep and clinically infected lower extremity ulcers, classified as Meggitt-Wagner class 3 or 4, Texas class 2C, 3C, 2D or 3D, or WIfI class W>1, I>1 and fI>0), present for at least 4 weeks or after a minor amputation because of a previously existing ischaemic DFU on a toe or forefoot. In case more than one ulcer is present, the largest will be observed as target ulcer Leg ischaemia, characterized by a highest ankle systolic blood pressure < 70 mmHg, or a toe systolic pressure < 50 mmHg or a TcpO2 < 40 mmHg Complete assessment of peripheral arterial lesions from the aorta to the pedal arteries with duplex ultrasonography, magnetic resonance angiography, computed tomography angiography and/or intraarterial digital subtraction angiography of the ipsilateral leg Patients have to be discussed in, and included after a multidisciplinary consultation. Adults Written informed consent Exclusion Criteria: Chronic Obstructive Pulmonary Disease (COPD) GOLD IV Treatment with chemotherapy, immunosuppressive drugs or systemic corticosteroids within last 3 months, as this interferes with normal wound healing End-stage renal disease requiring dialysis Metastasized malignancy Left ventricular failure with ejection fraction (EF) <20% or external pacemaker Recent thoracic surgery or middle ear surgery Severe epilepsy Uncontrollable high fever Pregnancy Insufficient proficiency of local language/English, or inability to complete the questionnaires

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
Interventional Model Description: Randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Control group | |
| Experimental: HBOT 20<br>Patients receiving 20 sessions of concurrent Hyperbaric oxygen treatment | Drug: Hyperbaric oxygen<br>* 90-120 min sessions of hyperbaric oxygen treatment of 2.2-2.5 ATA<br>|
| Experimental: HBOT 30<br>Patients receiving 30 sessions of concurrent Hyperbaric oxygen treatment | Drug: Hyperbaric oxygen<br>* 90-120 min sessions of hyperbaric oxygen treatment of 2.2-2.5 ATA<br>|
| Experimental: HBOT 40<br>Patients receiving at least 40 sessions of concurrent Hyperbaric oxygen treatment | Drug: Hyperbaric oxygen<br>* 90-120 min sessions of hyperbaric oxygen treatment of 2.2-2.5 ATA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Amputations | Major amputations, defined as below the knee or above the knee amputations | 12 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amputation-free survival | Time without amputation | Complete follow-up (up to 3 years) | 
| Health-related quality of life | Quality of life based on various questionnaires (objective) | Complete follow-up (up to 3 years) | 
| Complete wound healing | Complete wound healing | 12 months after inclusion | 
| Pain scores | Pain scores taken by VAS questionnaire | 12 months after inclusion | 
| Need for additional (vascular) interventions | Vascular interventions performed during time of inclusion | Complete follow-up (up to 3 years) | 
| Cost-effectiveness and budget impact | Costs of healthcare resources, including HBOT, related to the total number of eligible patients for HBOT per year. QALYs, based on EQ-5D-5L | Complete follow-up (up to 3 years) | 
| Mortality | Mortality | Complete follow-up (up to 3 years) | 
| Patients perception of improvement | Quality of life based on various questionnaires (subjective) | Complete follow-up (up to 3 years) | 
| TcpO2 before, during and after HBOT | Measurements of TcpO2 surrounding HBOT treatment | During intervention period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Foot Ulcer, Hyperbaric Oxygen, Peripheral Vascular Disease, HBOT, DFU, Major amputation, Diabetes, Ischemia