Title: Multiple Interventions for Diabetic Foot Ulcer Treatment (MIDFUT) Trial
Funder: Department of Health and Social Care

Abstract: DESIGN:Multi-centre, seamless Phase II/III, open, parallel group, multi-arm multi-stage RCT Randomisation: Via central 24hr automated service. Minimisation with random element in both Phases, stratified by centre, aetiology, ulcer duration, anatomical site & presentation Blinding: independent assessor to conduct outcome assessments; photography + digital planimetry of ulcer area; central blinded photography review of healing status SETTING: Multi-disciplinary DFU clinics TARGET POPULATION: Inclusion criteria: Aged>18; Diabetes Mellitus; chronic DFU or amputation; ulcer base not involving bone/joint; area>1cm2; ABPI>0.7; consent Exclusion criteria: Infection; HbA1C>110mmol/mol; eGFR>20mL/min/1.73m2; comorbidities affecting healing; planned revascularisation; previous growth factor treatment, revascularisation/foot surgery affecting healing >4 weeks; ulcer duration>2 years; expected non-compliance HEALTH TECHNOLOGIES: Phase II: 1.TAU control; 2.HD+TAU; 3.HD+7days NPWT+TAU; 4.HD+DCD+TAU; 5.HD+DCD+7days NPWT+TAU Phase III: TAU control; Up to 2 interventions from Phase II MEASUREMENT OF COSTS AND OUTCOMES: Phase II: Primary: >50% reduction in wound area at 4 weeks post randomisation Phase III: Primary: Time to healing of reference DFU Secondary: Proportion of DFU healed by 12/20/52 weeks; re-ulceration, infection, revascularisation, SAEs, amputation, admission to hospital and QoL (DFU-SF, EQ-5D-5L) at 4/12/20/52 weeks; health resource utilisation Follow-up visits at 2/4/12/20/52 weeks SAMPLE SIZE: Maximum of 660 patients recruited; 324 patients in Phase II; 336 patients in Phase III. Phase II: Effect size: absolute increase of 25% in the proportion of patients achieving 50% reduction in wound area by 4 weeks post randomisation (39% reach 50% reduction by week 4 in the TAU arm); 10% loss to follow-up Phase III: Effect size: hazard ratio of 1.5(median time to healing 21 weeks and 18% unhealed at 52 weeks with TAU); 2-sided 2% significance level (to control the family wise error rate at 5%), 10% loss to follow-up Overall power: ~83% and ~81% for recommending single & each of two effective interventions respectively ANALYSIS: Primary analyses on intention-to-treat patient population Phase II: Multivariable logistic regression fitted to achieving >50% reduction in wound area at 4 weeks with covariates for minimisation factors Phase III: Primary endpoint analysis: Cox Proportional Hazards regression model fitted to time to wound healing with covariates for minimisation factors and phase recruited. Deaths & amputations considered as competing risks; revascularisation considered as a time-dependent covariate Health Economics: cost of health & social care service utilization; incremental cost effectiveness ratios; within trial cost-effectiveness analysis CURRENT AND PLANNED CARE PATHWAYS: Care pathway for patients in both intervention and control arms of the trial will be the same and reflect NHS management responsibilities in MDT DFU clinics and community services. Patients will be screened, recruited and followed up during standard clinic visits. PROJECT TIMETABLES: Total 60 months (full trial): set-up 6 months, recruitment 22 & 12 months (Phase II & III respectively); follow-up 12 months; analysis 6 months. Recruitment rate:1-2 patients/month across 20 centres EXPERTISE IN TEAM: Multidisciplinary national team with clinical experts, methodologists (trialists, statisticians, health economist) & patient representative

Lay abstract: People with diabetes are at risk of developing diabetic foot ulcers (DFUs) which affect quality of life and can lead to serious complications including amputation (loss of foot/part of leg). The current approach to treatment is management in specialist clinics by teams with podiatrists, consultants, vascular surgeons etc. who provide a combination of treatments including: improving blood sugar control, removal of dead tissue and debris from the wound (known as wound debridement), dressings and protection of the area from harmful pressures. This is known as ‘best care’. Wounds that persist for more than 4 weeks are considered to be ‘chronic’ and are a significant burden to patients and the NHS. We plan to conduct a two-stage study in patients with DFUs to compare 3 treatments in 4 different combinations to ‘best care’, because it is not clear whether there are any benefits to them being used alone or together. In the first stage we will assess short-term benefits and drop at least 2 of the treatments. In the second stage we will assess long-term clinical benefit of up to 2 remaining treatments. In total we will recruit 660 patients attending DFU clinics. Each treatment will be undertaken in one treatment visit. Follow-up will be in standard clinics for 52 weeks and patients will continue to receive ‘best care’. The 3 treatments of interest are: Skin graft: we are assessing a skin graft material known as decellularised dermis (DCD), prepared from donated human skin which is processed, sterilised and frozen. Processing keeps the normal skin structure, but removes donor cells meaning that the graft has a low rejection response and is capable of serving as a permanent ‘implant’. It has become a possible treatment of DFUs for two reasons: the cost of DCD has been reduced and wound preparation previously required surgical wound debridement in an operating theatre. A clinic based alternative is now available. Surgical wound debridement: we do not know whether healing of DFUs can be improved by surgical debridement alone. A new technology has been developed whereby high pressure water is applied to debride the wound and fully expose a clean wound. The technique called hydrosurgery can be undertaken in clinic. Wound management: we would like to assess the use of a pump which ‘sucks’ moisture from the wound and keeps it clean, known as negative pressure wound therapy (NPWT). It is not a new technology, but is now available in a small portable pump strapped around the ankle and does not affect and normal activity. Sometimes following skin grafting and surgical debridement it is applied to the DFU for a week. We would like to know whether there is any benefit of NPWT alone or in combination with the other treatments. To assess benefits to patients a trial with one control and 4 treatment arms as follows: Control: ‘Best care’. Intervention arms: 1. Surgical debridement alone 2. Surgical debridement with NPWT 3. Surgical debridement with DCD 4. Surgical debridement with DCD and NPWT

Research activity codes: 6.3 MEDICAL DEVICES;6.4 SURGERY
Health categories: METABOLIC AND ENDOCRINE