Award Title: CODIFI2: Randomised controlled trial of swab versus tissue sampling for infected diabetic foot ulcers, and comparison of culture versus molecular processing techniques
Funder: Department of Health and Social Care

Abstract: Up to 1 in 4 people with diabetes will develop a foot ulcer related to their diabetes. Some ulcers become infected with bacteria, leading to pain, redness and delayed ulcer healing. If infection spreads it damages skin and bone in the foot and this can require surgery to remove infected tissues. Doctors, nurses and podiatrists are vigilant for any signs of infection and act quickly to clear the ulcer of infection, including prescribing antibiotics to fight the infection. _x000D_
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When infection is suspected the nurse or podiatrist will collect a specimen from the wound to send to a laboratory to identify the bacteria causing the infection. There are two ways to collect a wound sample: collecting wound fluid using a cotton swab (wound swab), or taking a small piece of wound tissue (tissue sample). Swabs are easier and this method is used the most. Many experts and practice guidelines recommend tissue sampling as it is better at collecting harmful bacteria. Previous studies have found tissue samples collect more bacteria than swabs, but also that swabs are less painful. Now that we know tissue samples collect more bacteria, we want to test whether this information helps clinicians make better decisions about which antibiotics to use. We will also see whether this helps clinicians better match the antibiotics to the infection, and so cure the infection and help the ulcer heal more quickly. _x000D_
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To make a fair comparison of swab versus tissue sampling we will aim to recruit 730 people with diabetic foot ulcer infection. The nurse or podiatrist will obtain a wound specimen by swab or tissue sample, as allocated by a computer. The doctors, nurses and podiatrists will decide on all aspects of each patient’s care, such as dressings, off-loading and any medications._x000D_
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We will follow these patients and collect information on their treatment, the ulcer infection, and the size of the ulcer (until the ulcer heals or 1-2 years later). All samples will be sent to the local laboratory to be grown and tested to see what antibiotics will work. We won’t include people with severe infection, anyone unable to consent or those with very old ulcers (more than 2 years)._x000D_
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We will follow-up patients at 4 weeks & at 6 months to see if their ulcer is reducing in size and see patients when their ulcer has healed. We will collect information on the ulcer, their overall health, and the treatments and care they have had for their foot ulcer, using a postal questionnaire and from hospital notes._x000D_
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During the CODIFI2 trial we will also study the impact of the letters asking people to complete postal surveys on completion rates. _x000D_
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We will take a 2nd wound sample to test for bacteria using genetic 'fingerprinting' techniques that look for bacteria DNA. This will tell us whether these tests find more bacteria than growing them in the laboratory, and if so, would this potentially change antibiotic treatment. The microbiology reports obtained from the molecular techniques will be used to discuss with clinicians in interviews how they would use the detailed information and whether they would replace traditional techniques with the modern methods, or prefer to use both.  The information obtained from the molecular techniques will be investigated to see if it helps us predict ulcer healing better than the factors we already know are important (e.g. large ulcers take longer to heal than small ulcers).  We will also look at the potential value of future research comparing genetic fingerprinting techniques to detect bacteria, compared with growing the bacteria in the laboratory.

Lay Abstract: Trial Design: Multi-centre, phase III, parallel group, randomised controlled trial in diabetic foot ulcer infection (DFU), including a 12month internal pilot phase (study 1) & study 2: diagnostic technique agreement study, virtual clinic study, prognostic model development, qualitative study and value of information analysis_x000D_
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Setting:UK multi-disciplinary DFU clinics_x000D_
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Inclusion criteria:age 18+, Type 1 or 2 diabetes; clinically suspected DFU infection;consent_x000D_
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Exclusion criteria:suspected osteomyelitis/severe infection; ulcer duration>2 years;previously randomised_x000D_
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*Study 1:Sampling Techniques_x000D_
Randomised (1:1 allocation) to policy of swab or tissue sampling for index & subsequent ulcers, using minimisation algorithm _x000D_
Blinding: Independent clinical assessor to conduct outcome assessments with blinded central photography review of the healing endpoint_x000D_
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Technologies being evaluated: _x000D_
Intervention 1:Wound swab with analysis by culture & antibiotic susceptibility (C&S)_x000D_
Intervention 2:Tissue sample with analysis by C&S_x000D_
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Primary outcome:Time to healing of index ulcer_x000D_
Secondary outcomes: Compliance with randomisation; healing status at 26 & 52 weeks (& at 104 weeks in people recruited in year1), area change at week 4, time on antibiotics, SAEs (amputation, osteomyelitis, hospital admission) & QoL (Diabetic Foot Ulcer Scale-Short Form & EQ-5D-3L)_x000D_
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Health Economic outcomes:Health resource utilisation (incl. antibiotics, cost of health & social services) and QALYs. _x000D_
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Follow-up visits: At week 4, 26 and healing. Record review, health resource & QoL at 4/8/12/26/39/52 and (for recruits in first year) 104 weeks_x000D_
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Sample Size: 730 participants are required to have 90% power to detect a minimum clinically important difference of 12.5% in the proportion healed at 12 months (centres on 45% healed at 12 months), assuming 2-sided, 5% significance level & 10% loss to follow-up_x000D_
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Analysis: Primary analyses on intention-to-treat patient population_x000D_
Primary endpoint analysis: Cox proportional hazards regression model fitted to time to healing with covariates for minimisation factors. Deaths and amputations will be considered competing risks and treatment effect will be estimated with respect to time to death and amputation-free healing. Revascularisation will be considered as a time dependent covariate_x000D_
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Health economic analysis: within-trial cost-effectiveness, cost per QALY, using EQ-5D utilities, NHS & PSS costs. Value of information of trial comparing molecular and culture techniques_x000D_
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During the trial we will also investigate the impact of modifying letters sent with patient questionnaires improves response rates (a study within a trial). _x000D_
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*Study 2:Processing Techniques_x000D_
 - A second wound sample (swab in those allocated to swab sampling at randomisation; tissue from those allocated to tissue sampling) will be sent to a central laboratory for molecular testing, thus we will have both swab and tissue samples with analysis by molecular methods and culture. We will compare microbiology results obtained via C&S and molecular methods to assess agreement. _x000D_
 - Results from C&S and molecular methods will be presented to clinicians in a ‘virtual clinic’ to ascertain their proposed antibiotic prescribing decision-stop/amend/continue. _x000D_
 - We will refine prognostic models of the relationship between clinical data plus bacterial profiles (via molecular methods), and patient outcomes. _x000D_
 - We will explore with clinicians the aspects of microbiology reports required to permit molecular techniques to replace, rather than be an adjunct, to culture (e.g. time to results, comprehensiveness)_x000D_
 - We will estimate the value of further research aimed at reducing the likely uncertainty surrounding the economic model’s parameters associated with molecular techniques vs plating and culture using a Value of information analysis approach (VOIA).

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION;METABOLIC AND ENDOCRINE