Title: ROSSINI II Trial - Reduction Of Surgical Site Infection using several Novel Interventions. A multi-arm, multi-stage surgical RCT utilising an adaptive design
Funder: Department of Health and Social Care

Abstract: Design: Multi-arm, multi-stage (MAMS) pragmatic multicentre RCT exploring the use of three in-theatre interventions to reduce SSI. Non-factorial design with allocation of various combinations of the three interventions to be used during the same operation, via seven possible treatment arms initially. Predefined interim analyses will be undertaken at two points during the trial; two arms will be dropped after each analysis. Setting: Multiple NHS hospitals in the UK. Target population: Adults undergoing abdominal surgery. Inclusion criteria: Adults undergoing abdominal surgery for any indication - including colorectal, hepatobiliary, upper GI, urological, vascular, gynae operations via any incision, both emergency and elective. Laparoscopic-assisted abdominal operations with a specimen extraction site of at least 5cm also eligible. Exclusion criteria: Age< 18 years; unable to give informed consent; previous laparotomy within the past 3 months. Health technologies being assessed and their control arms: 1) 2% alcoholic chlorhexidine skin prep – versus any other standard skin prep routinely used 2) Ioban-impregnated incise drape – versus none 3) Gentamicin-impregnated collagen implants at closure – versus none Outcomes: Primary – SSI within 30 days of surgery, assessed by blinded clinicians at 5-7 and 30-35 days, and by patient’s self-report for intervening period Secondary - Health-related quality of life assessed using the EQ-5D questionnaire, Health resource usage and the incremental cost-effectiveness of the interventions compared to standard care; Adverse events. Difference between current and planned care pathways: This pragmatic trial is designed to have minimal impact upon a patient’s standard clinical care and thereby enhance acceptability and recruitment levels, whilst maximising follow-up rates. The only additional procedures for this trial are as follows: i) consent and HR-QOL at baseline (pre-op) ii) in-theatre randomisation – to maintain blinding and minimise attrition/cross-over rates iii) in-person wound review by a blinded, clinically trained observer at 5-7 days (pre-discharge) and 30-33 days. Sample size: 6613 patients. Based on control arm SSI rate of 15% reduced to 10% in intervention arm(s); power 85%; FWER 0.025. Three stages; two interim and one final. First analysis at 2357 patients, second at 4632 pts. After each interim analysis two intervention arms dropped. Selection of arms to be dropped undertaken using a composite of clinician acceptability, adherence to arm allocation and clinical effectiveness. Project timetable: Funding is requested for a 48 month (4 year) project. 6 months - set up 6 months - internal pilot (10 sites) 32 months recruitment from 62 sites; opening sites at 4 per month during main phase; each open site recruiting 4 pts per month. 4 months - completion/final analysis Expertise: We have assembled a large and multidisciplinary research team to deliver this trial, with a proven track record in creating large surgical RCTs delivered through an established network of over 115 surgical units, who will work in close conjunction with the world leaders in complex trial design and analysis. The team also includes the founders and current leaders of trainee-led research, who will form an important core of trial management and delivery. There is also expert representation in health economics, microbiology and PPI, including service user representatives.

Lay abstract: Introduction This study aims to test in whether a group of simple interventions, alone or in combination, can reduce the chance of a patient developing a wound infection after surgery on the abdomen (tummy). Background Around a quarter of patients undergoing abdominal operations will develop an infection of the wound (also called a surgical site infection or SSI). If this occurs, they will need to stay in hospital for up to double the normal length to treat the infection, and they are likely to have increased levels of pain and subsequent hernia formation as well as cosmetically inferior scars. In rare cases an SSI can be very severe and cause or contribute towards a patients death after surgery. SSI is also a significant problem for the NHS, due to increased treatment costs and resource usage both in hospital and in the community. It is therefore a priority, and a current NHS quality target, to try and reduce SSI rates. There are many measures that surgeons can undertake during an operation to try to prevent SSI but very few of them have been subject to high quality testing. This is often because trials undertaken to investigate them are too small or are not generalisable to the wider population. Our trial has been carefully designed to investigate several interventions at once which makes it both cheaper and quicker than running several smaller separate trials. Design Three supplementary in-theatre interventions are being assessed. Patients participating the trial will be randomly allocated to receive all, none or some of these in any combination. They are: • Chlorhexidine 2% alcohol skin preparation - A strong cleaning solution to cleanse and sterilise the skin before surgery. Compared against any other standard skin preparation normally used. • An Iodophor-impregnated incise drape – A very thin plastic sheet stuck onto the skin before surgery and thought to prevent infection by trapping any bacteria left on the skin after preparation, as well as preventing new bacteria ingress. Compared against no drape. • Gentamicin-impregnated collagen implant - Small absorbable sponges placed in the wound at the end of the operation that slowly disintegrate and deliver antibiotics locally to try and kill any bacteria present that may go on to cause an SSI. Compared against no implant. It is possible that these interventions might have a cumulative effect. Our trial will both test each intervention and look in a rational fashion at how they might work together. Patient and public involvement There will be three named patient representatives on the trial design and management committee, ensuring that patients and their interests remain central. A new patient focus group will also review and optimise all patient-facing documentation such as information leaflets and consent forms. Dissemination The results will be used to advise surgeons how to best prevent surgical site infections. This may include recommending against the use of the above interventions if some or all are found not to work or be cost-effective. Results will be presented and published locally, nationally and internationally. The patient group will help create lay summaries of our findings for dissemination to trial participants and the wider population.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;6.3 MEDICAL DEVICES
Health categories: INFECTION