Title: Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their use in assessing clinical management.
Funder: Health Education England

Abstract: Worldwide the incidence of diabetes is rising. By 2035 the estimated prevalence of diabetes in the UK will be 7.4%1. Management of diabetic foot disease represents 0.6-0.7% of total NHS expenditure2. Charcot neuroarthropathy (CN) is a devastating complication of diabetes. It occurs as a result of peripheral neuropathy. It is a relatively painless progressive destructive arthropathy in a single or multiple joints in the foot. Amputation is a significant risk of CN with rates reported between 2.7%- 6.6% 3,4. Mortality is also increased; average life expectancy is reduced by 14.4 years compared to the general UK population5. There is controversy over the best way to monitor and treat this condition. The international consensus on treatment is to stop the inflammatory process, relieve pain and maintain foot architecture through the application of a non-removable device6. This immobilises the foot, minimising the potential for any further damage, but requires weekly or fortnightly review. Worldwide there is a significant variation in the median period of immobilisation; in the UK observational studies report durations of 9-12 months7,8 whilst data from the USA and other European centres report periods of immobilisation for only 4-6 months911. Such a prolonged period of immobilisation is a source of enormous social limitation and consequent reduction in quality of life. The aim of this study is to explore the feasibility of using serial MRI in an attempt to reduce the duration of immobilisation of the foot. The project is designed in two stages: a systematic review; and a feasibility study including qualitative interviews to gain insights into the patient's perspective of CN and involvement in the study. Because this is a feasibility study, a range of outcomes will be tested. Primary Outcomes will provide the information needed to design a future (post-doc) definitive RCT; Number of eligible patients recruited in the study period Sample size needed to power a definitive study Retention levels Willingness of clinicians to participate in study Follow up rates Secondary outcomes will test a range of clinical and patient related outcomes in preperation for the RCT; Days without a cast at the end of the study Charcot related outcome - deformity as documented by radiological angles, and development of new ulcers Patient-related outcomes pain visual analogue scale, SF-12 and survival Qualitative patient interviews Participants with diabetes and a diagnosis of active CN attending multidisciplinary diabetic foot clinics will be randomised to one of two arms: (a) cast immobilisation discontinued on the basis of MRI defined disease resolution at either 3, 6, 9 or 12 months (novel)(b) cast immobilisation discontinued on the basis of clinical remission determined by skin temperature measurement and MRI (standard care) The MRI result will be used as the criterion on which a decision will be made to discontinue casting in both groups. This will therefore evaluate whether the current practice of skin temperature measurement remains a valid test. The hypothesis is that serial MRIs allow the clinician to confidently take people out of cast sooner than waiting for clinical remission with temperature measurements. This feasibility study is a necessary first stage12 before considering whether a full scale pragmatic RCT is merited. If a future full scale RCT demonstrates that the use of MRI reduces treatment times there could be significant cost savings for the NHS. Patients would be able to return to work sooner reducing the societal impact of this condition, and improving the devastating impact that this disease has on the patients' quality of life and psychological well-being. If the use of MRI reduces treatment times by only 4 appointments this will off-set the cost of the additional investigations13

Lay abstract: Aim The aim of the study will be to assess the feasibility of the use of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes. Background The number of people with diabetes is rising rapidly. Longstanding poorly controlled diabetes causes lots of complications. For example people with diabetes are at twice the risk of developing strokes and heart attacks compared to people who do not have diabetes. Other complications include kidney disease, eye disease and nerve disease. Having the nerve disease that diabetes can cause tends to start in the smallest, finest nerves furthest away from the brain which tends to be the sensation nerves in the feet. This happens very slowly so people do not realise that they are losing sensation in their feet. Eventually the foot can become numb. This means that if the patient suffers any trauma then they may not notice it and they may continue to walk around on an injured foot. As with any other form of injury the foot will become hot, red and swollen. The bones then may start to rub together which leads to an inflammation within the bone. This condition is called Charcot neuroarthropathy and it is a devastating complication of diabetes for people who develop it. There are over 2000-2500 of new cases of Chracot neuroarthropathy diagnosed every year. If the inflammation goes on for long enough it can cause fractures and dislocations within the foot, which left untreated can lead to foot deformity and complications such as ulcerations. It is still poorly understood by health care professionals. Charcot neuroarthropathy is an expensive condition to treat costing the NHS 4million pounds per year. A diagnosis of Charcot neuroarhtropathy has been shown to reduce people's quality of life, and people who have had this condition die on average 14 years younger than the general population. Every year about 50-100 people who have been diagnosed with Charcot neuroarthropathy undergo an amputation of their leg. Charcot neuroarthropathy is treated by wearing a non-removable cast or walking boot. Patients require weekly or fortnightly review in clinic. No-one knows how long this treatment should last, some recommend 6 months, others more than a year. Early treatment has been shown to lead to fewer complications. There is some information from small studies that repeated assessment with magnetic resonance imaging may prove useful in helping clinicians decide when to stop treatment, and it may decrease treatment times. This needs to be formally investigated through a trial. Magnetic resonance imaging is a scan that uses strong magnetic fields and radio waves to produce detailed images of the inside of the body. Design and methods used This study will be a feasibility involving 50 people with diabetes and Charcot neuroarthropathy. Patients will be recruited from the Diabetic Foot Clinics at the Norfolk & Norwich and Derby Hospitals. Patients will be randomised (having an equal chance of being in one or the other group) to either receive magnetic resonance imaging at baseline 3, 6, 9 and 12 months or to receive current standard assessment using repeated foot temperature measurements and plain x-rays. If the study results indicate the study is feasible to do, the information will be used to design a much larger study in the future, designed to assess if the new treatment is effective, compared to standard treatment. The feasibility study will run for 3 years, with an 18 month recruitment period, and a further 18 months of follow-up. The effectiveness of treatment in preventing foot deformity will also be reported by looking at changes in plain x-rays over 18 months. The study will also assess patients' satisfaction, mood and well-being. Some patients will also be asked to participate in an interview at the end of the study, to gain insights into their experience of having Charcot neuroarthropathy and involvement in the study Two patient and public representative are part of this research team. The proposal here reflects their direct involvement with the trial design as well as that of a panel of patients and lay persons with diabetes. Dissemination I will disseminate the results of this feasibility study through established links with relevant national groups and professional organisations. I will publish the results in journals and present it at professional conferences. Findings will be shared with NHS funded bodies that make decisions about services. I will explore the use of modern social media techniques to provide updates on the study including twitter feeds from relevant professional and public groups.

Research activity codes: 6.3 MEDICAL DEVICES;7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE