DIONYSIUS trial: "Does increasing oxygen nurture your symptomatic ischaemic ulcer sufficiently?" Study protocol for an international multicentre randomised trial

INTRODUCTION: Diabetic foot ulcers (DFUs) are a major complication of diabetes and often associated with peripheral arterial occlusive disease. Current available evidence shows hyperbaric oxygen therapy (HBOT) can reduce the risk of major amputation, but clinicians remain sceptical about the (cost-)effectiveness and feasibility of HBOT for ischaemic DFUs in clinical practice. Therefore, vascular surgeons and HBOT physicians worldwide feel a strong need for a sufficiently powered clinical trial to determine whether and how many HBOT sessions may be a (cost-)effective adjunctive treatment to ischaemic DFUs. METHODS: An international, multicentre, multi-arm multi-stage design is chosen to conduct an efficient randomised clinical trial. 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 comprise 90-120 min of HBOT at a pressure of 2.2-2.5 atmospheres absolute according to international standards. Based on a planned interim analysis, the best performing study arm(s) will continue. Primary end point is major amputation (ie, above ankle) rate after 12 months. Secondary end points are amputation-free survival, wound healing, health-related quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: All patients enrolled in this trial will receive maximum vascular, endovascular or conservative treatment and local wound care according to best practice and (inter)national guidelines. HBOT therapy is added to the standard treatment and is regarded as a low-risk to moderate-risk therapy. The study is approved by the medical ethics committee of the Amsterdam University Medical Centers, location University of Amsterdam. TRIAL REGISTRATION NUMBER: 2020-000449-15, NL9152, NCT05804097.