ROSSINI 2

Surgical site infection (SSI) is a significant problem for patients and the health service, but is potentially preventable. Up to 25% of patients undergoing an abdominal surgical procedure develop an SSI and at an average cost of £3500 per SSI, it has been estimated that SSIs currently cost the NHS around £700 million per year, largely through prolonged postoperative inpatient stay and additional inpatient and outpatient treatment costs.

There is a significant health need for the ROSSINI 2 trial to address the problem of SSI, with benefit for both patients and the NHS. 

PILOT PHASE

ROSSINI 2 will have an Internal Pilot Phase recruiting 150 patients across 10 sites over 6 months.

The aims of the internal pilot trial are to assess:

1. if recruitment to the randomised interventions is feasible,
2. adherence to randomised intervention allocation,
3. if patient follow-up can be completed within protocol-specific timelines.

STOP/GO Criteria

The following criteria will be used to determine the feasibility of trial progression:

• Recruitment: At least 6 of the 10 pilot trial sites will achieve an average recruitment of 4 patients per month by the end of the pilot phase.
• Adherence: Investigators' adherence to arm allocation within all three intraoperative interventions and their combinations must be at least 80%.
• Follow-up: Timely completion and submission of Case Report Forms (CRFs) is crucial to allow interim analyses for the adaptive design. The ability to complete blinded, in-person primary outcome assessments at 30 days post-operation and data submission within 60 days of randomisation should be at least 70% by the end of the pilot phase.

MAIN PHASE III TRIAL

Primary objective

• To determine whether three specific in-theatre interventions, alone or in combination, result in decreased rates of surgical site infection (SSI) up to 30 days post-operation in adult patients undergoing abdominal surgery.

Secondary objectives

• Is the efficacy of the intervention/treatment arm dependant upon:
  • degree of wound contamination (clean, clean-contaminated, contaminated, dirty)?
  • patient comorbidity (e.g. diabetes, smoking, obesity)?
  • duration of operation?
  • stoma formation?
• Do the intraoperative interventions:
  • have an acceptable safety profile?
  • reduce the rates of wound complications?
  • reduce the rates of mortality?
• Does the use of the interventions, either alone or in combination:
  • improve health-related quality of life?
  • reduce the length of stay in hospital?
  • reduce wound complication related hospital re-admissions?
  • reduce the occurrence of unplanned wound reopening and/or re-operations?
  • are cost-effective?

Primary Outcome Measures

• Surgical site infection(s) up to 30 days post operation will be assessed by a trained blinded assessor, by patient’s self-report and defined according to the internationally accredited Centers for Disease Control and Prevention criteria (CDC). 

Secondary Outcome Measures

• 30-day postoperative mortality rate (POMR).
• 30-day postoperative wound complication rate (Clavien-Dindo classification).
• Serious Adverse Events up to 30 days.
• Length of hospital stay after surgery as measured from the date of surgery to the date of discharge.
• Hospital re-admission for wound related complications within 30 days.
• Occurrence of unplanned wound reopening and/or re-operations within 30 days post-operation.
• Preference-based QoL measure (EQ-5D-5L) at Baseline, Day 7 (or discharge) and Day 30.
• Cost effectiveness (using Resource Use questionnaire).

ROSSINI 2 is a Multi-arm, multi-stage (MAMS) pragmatic, multicentre, randomised controlled trial, with an internal pilot, exploring the use of three separate in-theatre interventions, use alone or in combination, to reduce SSI. A non-factorial design with allocation of various combinations of the three interventions to be used during the same operation, via seven possible intervention arms plus a control arm initially.

The trial would be the first of its kind in a surgical setting. In addition to generating new knowledge in our primary research area, by utilising this advanced design in the context of our relatively simple primary endpoint of SSI, it will also pave the way for future efficient and rapid trials in other aspects of surgical care.

The three interventions chosen in ROSSINI 2 impact different phases of perioperative case and as such can be used either in isolation or in conjunction with each other and although there may potentially be interaction between the interventions (positive or negative) they appear to be mechanistically disparate.

The interventions are:

• 2% alcoholic chlorhexidine skin prep
• Iodophor-impregnated incise drapes
• Gentamicin-impregnated implants/sponge

10 local NHS hospitals will participate in the pilot phase of ROSSINI 2 and at least 60 NHS hospitals in the UK will participant in the main phase of ROSSINI 2.

Approximately 6610 patients will be required to detect a 5% absolute risk reduction in the interventions arm(s) (15% to 10%) with 85% power.

Centre and surgeon eligibility

Any centre performing emergency and/or elective abdominal surgery will be eligible to participate in ROSSINI 2. Sites entering the trial must not be routinely using these interventions and be willing to accept patients being randomised to receive (or not receive) each of them, including combinations thereof. Surgeons must be willing to adhere to arm allocation and be willing to be trained in a standardised application technique.

Patient Inclusion Criteria

• Patients undergoing colorectal, hepatobiliary, upper GI, urological, vascular, or gynaecological operations.
• Patients undergoing abdominal operations (open or laparoscopic extraction site) with a planned incision of at least 5cm.
• Patients aged 16 years or older.
• Patients able and willing to give written informed consent.
• All contamination strata, including clean, clean-contaminated, contaminated or dirty surgery.
• Patients undergoing planned (elective or expedited) or unplanned (emergency) surgery.

Patient Exclusion Criteria

• Previous laparotomy within 3 months prior to randomisation.
• Patients with a new or documented allergy/intolerance to any of the study interventions (chlorhexidine, iodine, collagen, or gentamicin) will not be randomised to an arm containing this intervention, but will still be eligible for recruitment to other arms of the study.
• Patients with end-stage renal failure where gentamicin administration would otherwise be contra-indicated (according to local policy) will not be randomised to arms containing the gentamicin-impregnated sponge.

The ROSSINI 2 Trial involves several types of training:

• Study-specific - this is provided by the ROSSINI 2 team during the Site Initiation Visit (SIV). It will be face-to-face whenever possible and ideally near the time of opening. Once, open, further study-specific training (i.e. new staff) can be delivered via teleconference by the ROSSINI 2 team or disseminated by the PI.
• Intervention application training - this will be provided by the CI and/or surgical trainees during the SIV. Once open, intervention application training (i.e. for new staff) is to be disseminated by the PI. Training materials will be provided

 The above types of training must be completed BEFORE a site can open to recruitment.

• Wound-assessment training - this is delivered online but is currently in development and hoped to be available soon.

The above training must be completed by anyone who will be reviewing the wound of trial participants.

The suppliers of the interventions used in ROSSINI 2 are:

ROSSINI 2 - Intervention Suppliers

Intervention	Supplier
2% Alcoholic Chlorhexidine skin prep (SKIN PREP)	Becton Dickinson UK Ltd (BD
Iodophor-impregnated incise drape (DRAPE)	3M United Kingdom PLC
Gentamicin-impregnated implants (SPONGE)	SERB

This study is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) (Grant Reference Number 16/31/123). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

If you are a site open to ROSSINI 2 you can randomise 24 hours a day, 7 days a week. This can be done either by phone or online. The randomisation service is provided by the Centre for Healthcare Randomised Trials (CHaRT), located in the Health Services Research Unit (HSRU) at the University of Aberdeen.

Telephone Randomisation - call 0800 2802 307

You will need to know your centre/site ID code and your own unique ID code, and be required to enter these at the start of the call. This will be available from your local PI and their team, and also from the ROSSINI 2 Trial Office.

Online randomisation - visit https://w3.abdn.ac.uk/hsru/ROSSINI2

Please find below links to important ROSSINI 2 trial documents.

• ROSSINI 2 Trial Protocol version 1.0, 02-Dec-2018

If you experience any difficulty accessing any content above, please contact the ROSSINI 2 team.