A Phase III, Multi-arm, Multi-stage (MAMS), Pragmatic, Blinded (Patient and Outcome Assessor), Multicentre, Randomised Controlled Trial (RCT) With an Internal Pilot, to Evaluate the Use of Several In-theatre Interventions, Used Alone or in Combination, to Reduce SSI Rates in Patients Undergoing Abdominal Surgery.
Phase: PHASE3
Conditions: Surgical Site Infection, Surgical Wound Infection, Surgery--Complications, Surgery
Sponsor: University of Birmingham

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ROSSINI 2: Reduction Of Surgical Site Infection using 
several Novel Interventions 
 
 
A phase III, multi-arm, multi-stage (MAMS), pragmatic, blinded (patient and 
outcome assessor), multicentre, randomised controlled trial (RCT) with an internal 
pilot, to evaluate the use of several in-theatre interventions, used alone or in 
combination, to reduce SSI rates in patients undergoing abdominal surgery. 
 
 
This protocol has regard for the HRA guidance and is compliant with the SPIRIT 
guidelines (2013). 
 
 
 
 
 
 
 
 
 
 
 
Version Number: 
3.0 
Version Date: 
12th July 2022 
TRIAL PROTOCOL 

 
 
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Protocol Development 
 
 
 
 
 
 
 
 
 
FUNDING AND SUPPORT IN KIND 
 
Funder 
Financial and non-financial support 
given: 
National Institute of Health Research 
University of Southampton 
Alpha House 
Enterprise Road 
Southampton 
SO16 7NS 
Financial; investigator led grant 
Funding scheme 
NIHR Health Technology Assessment 
(HTA) Programme 
Funder’s reference number 
16/31/123 
The Funder of this trial has no role in the trial 
design, data collection, data analysis, data 
interpretation or in the writing of the final 
report. 
This project is funded by the NIHR HTA 
Programme. The views expressed are those of 
the author(s) and not necessarily those of the 
NIHR or the Department of Health and Social 
Care 
 
 
SUPPLIERS 
Becton Dickinson UK Ltd (BD) 
Supplier of 2% Alcoholic Chlorhexidine 
skin prep [SKIN PREP] 
3M United Kingdom PLC 
Supplier of Iodophor - impregnated incise 
drape [DRAPE] 
SERB 
Supplier of Gentamicin - impregnated 
sponge [SPONGE] 

 
 
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Protocol Sign Off  
 
Chief Investigator (CI) Signature Page 
I, the Chief Investigator, confirm that I have read and agree with the following protocol, and 
that I will conduct the trial in compliance with the version of the protocol approved by the REC 
and any other responsible organisations. 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any other purpose other than the evaluation or conduct of the clinical investigation without 
the prior written consent of the Sponsor. 
 
I also confirm that I will make the findings of the trial publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the trial will be given; and that any discrepancies from the trial as 
planned in this protocol will be explained. 
Trial Name: 
ROSSINI 2 
Protocol Version Number: 
Version 3.0 
Protocol Version Date: 
12th July 2022 
CI Name: 
Professor Thomas Pinkney 
Signature and date: 
_________________________      __ __ / __ __ / __ __ __ __  
Sponsor statement: 
By signing the IRAS form for this trial, University of Birmingham, acting as sponsor of this 
trial confirm approval of this protocol. 
Compliance statement: 
This protocol describes the ROSSINI 2 trial only. The protocol should not be used as a guide 
for the treatment of participants not taking part in the ROSSINI 2 trial.  
 
The trial will be conducted in compliance with the approved protocol, UK Policy Framework 
for Health and Social Care Research, the Data Protection Act 2018 and the Principles of Good 
Clinical Practice (GCP) as set out in the UK Statutory Instrument (2004/1031) and 
subsequent amendments thereof. Every care has been taken in the drafting of this protocol 
but future amendments may be necessary, which will receive the required approvals prior to 
implementation. 
 
 
 

 
 
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Principal Investigator (PI) Signature Page 
As Principal Investigator, I confirm that the following protocol has been agreed and accepted, 
and that I will conduct the trial in compliance with the approved protocol where this does not 
compromise participant safety.  
 
I agree to ensure that the information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of the Sponsor. 
Trial Name: 
ROSSINI 2 
Protocol Version Number: 
Version 3.0 
Protocol Version Date: 
12th July 2022 
PI Name: 
 
Name of Site: 
 
Signature and date: 
_________________________     __ __ / __ __ / __ __ __ __  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Protocol Amendments 
The following amendments and/ or administrative changes have been made to this protocol 
since the implementation of the first approved version.  
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Summary of amendment 
SA_01 
18th July 
2020 
V2.0 
- Addition of COVID-19 sections throughout 
to provide information on risks (none), 
further secondary objectives and changes to 
patient pathway 
- Addition/ Change of Staff 
- Minor word changes for clarification 
purposes 
- Clarification regarding secondary objectives 
- Update of intervention guidelines 
- Modification to inclusion criteria  
- Modifications to exclusion criteria to exclude 
pregnant, breastfeeding patients and 
operations where the wound is not 
anticipated to be closed primarily 
- Additional section provided for clarity on 
eligibility  
- Clarification to patient pathway throughout 
- Additional section provide regarding bovine 
collagen within the SPONGE 
- Clarification provided regarding follow up 
beyond the primary trial window 
- Clarification regarding withdrawal from the 
trial 
- Clarification regarding Safety Reporting 
- Clarification regarding Data handling 
- Additional section relating to Protocol Non- 
Compliances 
- Clarification regarding the NIHRs Associate 
PI Scheme 
SA_02 
12th July 
2022 
V3.0 
- Stage 2 Summary of Completion (First 
Interim Analysis) provided 
- Addition of remote Consent 
- Implementation of Patient Reminder Cards 
- Clarification regarding the conduct of 
Wound Assessments  
- Update to Trial Schedule of Assessments 
- Further clarification provided regarding 
follow up beyond the primary outcome 
assessment window 
- Minor word changes for clarification 
purposes 
 
 
 

 
 
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Administrative Information 
 
CHIEF INVESTIGATOR 
Professor Thomas Pinkney 
George Drexler & Royal College of Surgeons 
Chair 
of 
Surgical 
Trials, 
and 
Honorary 
Consultant Colorectal Surgeon 
University 
Hospitals 
Birmingham 
NHS 
Foundation Trust 
  0121 415 9100 
 Thomas.Pinkney@uhb.nhs.uk  
 
INDEPENDENT DATA MONITORING AND ETHICS COMMITTEE 
Professor Michael Campbell (CHAIR) 
Emeritus Professor of Medical Statistics 
University of Sheffield 
Professor Nigel Hall 
Associate Professor of Paediatric Surgery 
University of Southampton 
Professor Ian Chetter 
Professor of Surgery and Director of 
Research 
University of Hull 
 
 
TRIAL STEERING COMMITTEE 
Professor David Beard (CHAIR) 
Professor of Musculoskeletal Sciences 
University of Oxford  
Professor Jane Nixon 
Professor of Tissue Viability and Clinical Trials 
Research University of Leeds 
Miss Sue Blackwell (PPI) 
 
 
 
 
 
 
 
 
SPONSOR 
University of Birmingham 
 
Research Governance Team 
University of Birmingham 
Birmingham 
B15 2TT 
 researchgovernance@contacts.bham.ac.uk  
 0121 414 7618 

 
 
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TRIAL MANAGEMENT GROUP 
TRIAL MANAGEMENT AND METHODOLOGY 
Professor Thomas Pinkney 
George Drexler & Royal College of 
Surgeons Chair of Surgical Trials 
University of Birmingham 
Professor Dion Morton 
Barling Professor of Surgery 
University of Birmingham 
Professor Peter Brocklehurst  
Director, Birmingham Clinical Trials Unit 
University of Birmingham  
Professor Max Parmar 
Professor of Medical Statistics and 
Epidemiology 
University College London  
Dr Kelly Handley 
Senior Medical Statistician 
University of Birmingham Clinical Trials Unit 
Dr Babak Choodari-Oskooei 
Medical Statistician 
University College London  
Dr Laura Magill 
Senior Lecturer in Clinical Trials 
University of Birmingham Clinical Trials Unit  
Mrs Manjinder Kaur 
Trials Management Team Leader 
University of Birmingham Clinical Trials Unit 
Miss Kayley King 
Senior Trial Manager 
University of Birmingham Clinical Trials Unit 
 
SURGERY 
Mr Aneel Bhangu  
University of Birmingham 
Miss Elizabeth Li  
University of Birmingham  
Mr Richard Wilkin  
University of Birmingham  
Mr Neeraj Lal  
University of Birmingham  
Mr Pritam Singh  
University Hospitals Birmingham 
Mrs Georgia Layton 
University of Birmingham 
Mr Dmitri Nepogodiev  
University of Birmingham 
Mr James Glasbey  
University of Birmingham 
Miss Arooj Syed 
University Hospitals Birmingham NHS 
Foundation Trust 
Miss Fatima Mansour 
West Midlands Research Collaborative 
Miss Nichola Manu 
University of Warwick 
 
HEALTH ECONOMICS 
Dr Lazarus Andronis 
Associate Professor of Health Economics 
University of Warwick 
 

 
 
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MICROBIOLOGY 
Dr Martin Gill 
Microbiologist 
University Hospitals Birmingham 
 
 
PATIENT REPRESENTATIVE 
Mr Leon Pollock  
Mr Pete Wheatstone 
Dr Samantha Cole 
 
 
TRIAL OFFICE CONTACT DETAILS 
Kayley King 
Senior Trial Manager 
Megan Garbett 
Senior Data Manager 
TBC 
Data Manager 
Birmingham Clinical Trials Unit 
Institute of Applied Health Research 
Public Health Building 
University of Birmingham 
Birmingham 
B15 2TT  
 0121 415 8840 
 0121 415 8871 
 rossini2@trials.bham.ac.uk  
 
Randomisation Service 
 0800 2802 307 
 https://w3.abdn.ac.uk/hsru/ROSSINI2 
Trial website 
 www.birmingham.ac.uk/rossini2  
 
 
REFERENCE NUMBERS 
Sponsor number  
RG_18-186 
ISRCTN reference number 
78305317 
Clinicaltrials.gov reference number 
NCT03838575 
IRAS reference number 
247285 
CPMS number 
39722 
 
 
 
  
 
 
 
 
 
 
 

 
 
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ABBREVIATIONS 
ABBREVIATION 
TERM 
ABPI 
The Association of the British Pharmaceutical Industry 
AMR 
Antimicrobial Resistant  
API 
Associate Principal Investigator 
APR 
Annual Progress Report 
BCTU 
Birmingham Clinical Trials Unit 
CCG 
Clinical Commissioning Groups 
CDC 
Centers for Disease Control and Prevention 
CEAC 
Cost Effectiveness Acceptability Curve 
CHaRT 
The Centre for Healthcare Randomised Trials 
CHG 
Chlorhexidine Gluconate 
CI 
Chief Investigator 
CPMS 
Central Portfolio Management System 
CQUIN 
Commissioning for Quality and Innovation 
CRF 
Case Report Form 
CTU 
Clinical Trials Unit 
DCF 
Data Clarification Form 
DMC 
Data Monitoring Committee 
DSA 
Data Sharing Agreement 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
GRIPP 
Guidance for Reporting Involvement of Patient and the Public 
HRA 
Health Research Authority 
ICER 
Incremental Cost Effectiveness Ratio 
ICF 
Informed Consent Form 
ISF 
Investigator Site File 
MAMS 
Multi-arm, Multi-stage 

 
 
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MRC CTU 
Medical Research Council Clinical Trials Unit 
NHS 
National Health Service 
NICE 
The National Institute for Health and Care Excellence 
NIHR 
National Institute for Health and Care Research 
PI 
Principal Investigator  
PIS 
Patient Information Sheet 
PNC 
Protocol Non-Compliance 
POMR 
Perioperative Mortality Rate (POMR) 
PPI 
Patient and Public Involvement 
PRC 
Patient Reminder Card(s) 
QALY 
Quality-adjusted life year 
QoL 
Quality of Life 
RCT 
Randomised Controlled Trial  
REC 
Research Ethics Committee 
RGT 
Research Governance Team 
RUQ 
Research Use Questionnaire 
SAP 
Statistically Analysis Plan 
SSI 
Surgical Site Infection 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UHB 
University Hospitals Birmingham 
UoB 
University of Birmingham 
WHO 
World Health Organization 
WHQ 
Wound Healing Questionnaire 
 
 
 
 
 

 
 
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DEFINITIONS 
Term 
Abbreviation 
Description 
Quality Management 
System 
QMS 
A Quality Management System (QMS) is a 
system that includes procedures and policies 
to describe how certain tasks should be 
performed 
and 
that 
encapsulate 
any 
standards and/or regulatory requirements 
that may apply to those tasks. By adhering 
to the Quality Management System, the user 
and the UoB will be assured that applicable 
regulations are adhered to.  
REDCap 
 
REDCap is a secure web platform for 
building and managing online databases and 
surveys, used within ROSSINI 2. 
Source documents 
 
All information in original records and 
certified copies of original records of clinical 
findings, observations, or other activities in 
a 
clinical 
trial 
necessary 
for 
the 
reconstruction and evaluation of the trial 
Birmingham Clinical 
Trials Unit 
BCTU 
The co-ordinating centre for the trial. 
EQ-5D-5L 
 
A standardized instrument for use as a 
measure of health outcome. 
SKIN PREP 
 
2% alcoholic chlorhexidine skin preparation 
provided by Carefusion/BD. 
DRAPE 
 
Iodophor-impregnated incise drape 
provided by 3M. 
 
Only applicable in Stage 1 (Pilot) and Stage 
2 (up to Interim Analysis 1). 
SPONGE 
 
Gentamicin-impregnated sponge provided 
by SERB. 
Stage 1  
 
Stage 1 refers to the Pilot Stage of the trial. 
Please see section 3.2 for the Pilot Stage 
Summary of Completion. 
Stage 2  
 
Stage 2 is beyond the Pilot Stage and up to 
the first interim analysis.  
 
See section 3.3 for Stage 2 Summary of 
Completion (First Interim Analysis) 

 
 
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Term 
Abbreviation 
Description 
Stage 3  
 
Stage 3 is beyond the first interim analysis 
and up to the second interim analysis.  
Stage 4 
 
Stage 4 is beyond the second interim 
analysis and up to final analysis. 
 
 

 
 
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TRIAL SUMMARY 
Title 
ROSSINI 2 - Reduction Of Surgical Site Infection using several Novel Interventions 
 
Primary Objective 
To determine whether several specific in-theatre interventions, used 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. 
 
Trial Design 
Multi-arm, multi-stage (MAMS), pragmatic, multicentre, randomised controlled trial, with an 
internal pilot, exploring the use of several specific in-theatre interventions, used alone or in 
combination, to reduce the rates of SSIs. A non-factorial design with allocations to various 
combinations of the trial interventions to be used during the same operation. 
 
Trial Setting 
At least 60 NHS hospitals in the UK will participate in ROSSINI 2. 
 
Participant Population and Sample Size 
Approximately 6610 patients will be required to detect a 5% absolute risk reduction in the 
intervention arm(s) (15% to 10%; 33% relative reduction) with 85% power. 
 
Key Eligibility Criteria 
 
Inclusion Criteria 
Patients 16 years or older, undergoing abdominal surgery of any level of contamination, both 
emergency and elective (open or laparoscopic assisted) with a planned incision of at least 5cm 
are eligible. Patients must be able and willing to give written informed consent and be available 
for a wound assessment at day 30-37.* 
 
Exclusion Criteria  
Patients with a previous laparotomy within 3 months prior to randomisation, pregnant or 
breast feeding and wounds not closed primarily. 
 
*Patients with a new or documented allergy/intolerance to any of the trial interventions 
(chlorhexidine, 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 trial.  
 
Interventions 
Several health technologies will be assessed versus the control arm (standard care):  
 
1. 2% alcoholic chlorhexidine skin preparation, versus any other standard skin 
preparation 
2. Iodophor-impregnated incise drape, versus no drape 
3. Gentamicin-impregnated sponge at closure, versus no sponge 
 

 
 
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Please note: In January 2022, following the first interim analysis, arms including intervention 
2 – Iodophor-impregnated incise drape (arms C, E, G and H) were closed to recruitment.  
 
Outcome Measures 
Primary: 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:  
• 
30-day postoperative mortality rate (POMR). 
• 
30-day postoperative wound complication rate (Clavien-Dindo classification). 
• 
Serious Adverse Events up to 30 days (wound or intervention-related only). 
• 
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 Quality of Life (QoL EQ-5D-5L) measured at Baseline, Day 7 (or 
discharge if sooner) and Day 30. 
• 
Cost effectiveness (Resource Use Questionnaire (RUQ)) 
 
Sub Study Objective 
• 
Is there microbiological ratification of the clinical findings in terms of pathogenic 
organisms prevented/not prevented by use of the interventions or combinations of 
interventions? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Summary of arms currently open to recruitment (Protocol V3.0) 
ARM 
INTERVENTION 
SUMMARY 
FROM 
PROTOCOL 
VERSION 
A 
NONE (Control) 
All patients undergoing an abdominal 
operation will have their skin prepared using 
some form of antiseptic skin preparation. 
Only in participants randomised to the trial 
intervention of 2% Alcoholic Chlorhexidine 
(arms B or F) should this skin preparation 
be used. For all other participants, they 
should receive the surgeon’s choice of skin 
preparation as long as this is NOT 2% 
Alcoholic Chlorhexidine. Other commonly 
used agents include 0.5% chlorhexidine or 
povidone-iodine, in aqueous or alcoholic 
solution. Concentrations and volumes of 
preparations vary and can be mixed in 
theatre or used as pre-prepared solutions. 
No other impregnated sponges should be 
used. 
V1.0 
B 
SKIN PREP 
2% alcoholic chlorhexidine skin preparation 
V1.0 
D 
SPONGE 
Gentamicin-impregnated sponge  
V1.0 
F 
SKIN PREP and 
SPONGE 
2% alcoholic chlorhexidine skin preparation 
and Gentamicin-impregnated sponge  
V1.0 
 
Summary of arms closed to recruitment (Protocol V3.0) 
ARM 
INTERVENTION 
SUMMARY 
TO 
PROTOCOL 
VERSION 
C 
DRAPE 
Iodophor-impregnated incise drape  
V2.0 
E 
SKIN PREP and DRAPE 
2% alcoholic chlorhexidine skin preparation 
and Iodophor-impregnated incise drape 
V2.0 
G 
DRAPE and SPONGE 
Iodophor-impregnated incise drape and 
Gentamicin-impregnated sponge  
V2.0 
H 
SKIN PREP and DRAPE 
and SPONGE 
2% alcoholic chlorhexidine skin preparation 
and Iodophor-impregnated incise drape and 
Gentamicin-impregnated sponge  
V2.0 

 
 
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TRIAL SCHEMA 
Figure 1.0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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BACKGROUND AND RATIONALE ................................................................ 21 
 
AIMS AND OBJECTIVES ............................................................................. 28 
 
TRIAL DESIGN AND SETTING .................................................................... 31 
 
ELIGIBILITY .............................................................................................. 35 

 
 
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CONSENT ................................................................................................... 37 
 
RECRUITMENT, SCREENING AND RANDOMISATION ................................ 39 
 
TRIAL INTERVENTIONS ............................................................................. 43 
 
OUTCOME MEASURES AND TRIAL PROCEDURES ....................................... 49 
 
ADVERSE EVENT REPORTING .................................................................... 56 

 
 
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DATA HANDLING AND RECORD KEEPING .................................................. 63 
 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 67 
 
END OF TRIAL DEFINITION ....................................................................... 70 
 
STATISTICAL CONSIDERATIONS ............................................................... 70 
 
Health economic analysis .......................................................................... 78 

 
 
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TRIAL ORGANISATIONAL STRUCTURE ...................................................... 80 
 
ETHICAL CONSIDERATIONS ...................................................................... 82 
 
CONFIDENTIALITY AND DATA PROTECTION ............................................. 83 
 
FINANCIAL AND OTHER COMPETING INTERESTS ..................................... 84 
 
INSURANCE AND INDEMNITY ................................................................... 84 
 
SUB-STUDIES ............................................................................................ 84 
 
ACCESS TO FINAL DATA SET ...................................................................... 85 
 
PUBLICATIONS AND OUTPUTS .................................................................. 85 
 
Associate Principal Investigator Scheme ................................................... 87 
 
Reference List ............................................................................................ 88 
 
Table of Appendices ................................................................................... 93 
Appendix 1. Superseded Trial Schema ................................................................. 94 
 
 

 
 
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 BACKGROUND AND RATIONALE 
 Background 
 
Surgical site infection after abdominal surgery 
Surgical site infection (SSI) is a significant problem for patients and the health service, but is 
potentially preventable. At least 5% of patients undergoing a surgical procedure develop an 
SSI; with over 4 million operations in the UK annually this represents a minimum of 200,000 
patients affected (3). At an average cost of £3500 per SSI, it has been estimated that SSIs 
currently cost the NHS around £700 million per year (4-6), largely through prolonged 
postoperative inpatient stay and additional inpatient and outpatient treatment costs (7, 8). 
 
It is increasingly recognised that SSI incidence is widely underreported. Traditional monitoring 
relies heavily on passive surveillance with minimal review after discharge, but at least 60% of 
SSIs present in the community after discharge. Out of hospital SSI events are therefore often 
unaccounted for (9). With the increase of enhanced recovery programmes and shorter lengths 
of stay, the proportion of SSIs presenting outside of hospital has increased further. Rates of 
SSI vary significantly between different types of surgery, but is particularly prevalent in 
abdominal operations; as many as one in four patients get an SSI when the operation involves 
the bowel (10).  
 
 
Impact of surgical site infection 
There is a significant health need for research to address the problem of SSI, with benefit for 
both patients and the NHS. SSI is associated with considerable morbidity, a reduction in quality 
of life and increased healthcare costs, and places a significant burden on healthcare systems 
and individuals. It has also been shown to be an independent predictor of mortality (11) and 
in 2002 there were 8,205 deaths in the US due to SSI, accounting for 8% of all deaths caused 
by a nosocomial infection (12, 13). Development of an SSI significantly increases duration and 
cost of patient hospitalisation, predominantly due to re-operation, additional nursing care and 
drug treatment costs (4-6). There is an additional societal burden of SSI, delaying return to 
work or normal activity and increasing care burden (7). 
 
 
Strategies to reduce SSI 
Preventing SSI is a complex process which is affected by interventions throughout the surgical 
care pathway. SSI reduction measures when bundled, or poorly implemented can be 
ineffective (14) or even increase SSI risk (15). A large proportion of SSIs are known to be 
caused by wound contamination by endogenous bacteria from the patient’s skin, or cross-
contamination from mucous membranes, hollow viscera, free pus or bowel contents (16). This 
has resulted in the development of many intraoperative interventions to try to decrease this 
contamination and thereby decrease SSI rates. Unfortunately, clinical studies exploring the 
efficacy of many of these interventions are often underpowered or poorly designed, or used 
in low risk groups leaving uncertainty if they are clinically and cost-effective. ROSSINI 2 aims 
to study simple biologically plausible interventions that may decrease SSI rates after 
abdominal surgery, but currently lack evidence in controlled studies. In this high-risk group, 

 
 
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SSI reduction benefits seen will bring the greatest rewards, both clinical and financial, and 
findings should be generalisable to other types of surgery. 
 
 
ROSSINI 1 trial 
The ROSSINI 1 trial recruited 760 patients from 21 UK centres from 2010 to 2012 (1). ROSSINI 
1 established several pathways that will support the delivery of a trial of multiple intraoperative 
interventions aimed at SSI reduction:  
• 
Data collection systems for blinded wound reviews, both before and after discharge, 
as well as the patient-reported wound survey to cover the intervening period. 
• 
Wound assessment online training resources, to educate and accredit wound assessors 
to the same standards (17). This reduces inter-rater variability and ensures an 
inherently subjective endpoint is as reliable as possible.  
• 
In-theatre randomisation, thereby helping to maintain blinding of outcome assessors, 
and minimising drop-out and treatment crossover.  
• 
Created a national network of research-active surgical trainees, with GCP training and 
the skillset to recruit patients to other randomised trials (18, 19).  
 
 Trial Rationale 
 
Benefits to patients 
SSI is the most common nosocomial infection worldwide (20) and effects patients across all 
settings (21). It delays hospital discharge and return to work, causes significant pain and 
discomfort and has a significant and lasting impact on patients’ quality of life (22). SSI can 
have serious consequences; patients are twice as likely to die as those without SSI and around 
one third of postoperative deaths are attributable, at least in part, to SSI (6). Antimicrobial 
resistant infections (AMR), the focus of a recent Lancet commission, are increasing at an 
alarming pace, and pose a great threat to patients and healthcare systems alike (23). In 2016, 
an international cohort study suggested that one fifth of SSI (21.6%) were resistant to the 
prophylactic antibiotic used at time of surgery (16). Effective SSI prevention strategies that 
can be used across diverse settings will reduce the burden of antibiotic use and mitigate the 
global impact of AMR. 
 
 
Benefits to the health service 
This major, multicentre, multi-arm, multi-stage (MAMS) trial with the opportunity to drop (and 
introduce) arms 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 outcome of SSI, it will also pave the way for future efficient 
and rapid trials in other aspects of surgical care. This major trial has a broad inclusion criteria 
and will be easy to recruit to at every UK hospital where elective or emergency operations 
take place. It will be disseminated and driven both by surgical trainees and Clinical Research 
Network staff and will involve participation from many new surgical investigators at both 
consultant and trainee level. Surgeons undertaking abdominal surgery of any type will be able 
to participate. It is likely that this trial would serve to further improve the quality and quantity 
of surgical clinical research in the UK and in so doing significantly benefit patients in the future.  

 
 
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Why the trial is needed now 
The detrimental impacts of SSI have been the subject of heightened interest over the past 
decade, and are the subject of an updated NICE quality standard published in 2017 (24). This 
document describes SSI as a high-priority area for quality improvement and suggests that 
commissioners may adopt SSI rates as a CQUIN (Commissioning for QUality and INnovation) 
target. We know that at least 10 Clinical Commissioning Groups (CCGs) have gone on to 
include SSI reduction as a CQUIN target in this manner (25). SSI is also the target of an 
ongoing national consultation and audit process targeted at looking at reduction in SSI practice 
and highlighting areas for improvement in quality of care (26, 27). SSI will remain an area of 
significant and sustained attention for both clinicians and providers, further strengthening the 
relevance and importance of this trial.  
 
 
Justification for participant population 
Recent high-quality prospective registries and randomised trials in abdominal surgery with 
comprehensive post-discharge follow-up have shown consistently high SSI rates of 22-26% 
(1, 15, 28-40). By targeting this high-risk population, where operative field contamination is 
common a clinically significant benefit is most likely to be identified. 
 
 
Justification of a multi-arm multi-stage design  
SSI prevention lends itself well to an adaptive or multi-arm, multi-stage (MAMS) trial design, 
because the primary outcome result is, by definition, available 30 days after the intraoperative 
intervention is applied. Interim analyses can exploit this short timeline to create an efficient 
trial that will evaluate several interventions (both individually and in combination) under a 
single umbrella structure. This decreases both the time and cost investment necessary to 
simultaneously determine if several non-bundled interventions are effective (41-44). 
Determining small incremental benefits will be slow and difficult to achieve. This trial design 
allows exploration of interactions between interventions, which each have a different biological 
mechanism in this multifactorial process. 
 
 
Choice of interventions and controls 
A series of systematic reviews have been undertaken and combined with current national and 
international guidelines to select the interventions being assessed in this trial, considering 
current NHS policy. The three relevant guidelines to this trial are: 
 
• 
WHO Surgical Site Infection prevention (45) 
• 
Centers for Disease Control (CDC) and Prevention Guidelines for the prevention of SSI 
(46) 
• 
NICE Clinical Guideline 74: Prevention and treatment of SSI (24) 
 
All of the interventions chosen to be assessed in ROSSINI 2 have demonstrated the potential 
to decrease SSI, yet lack the evidence base to be recommended in international guidelines 
and do not form current standard practice in the UK. A prospective one-week snapshot audit 
of current usage of the trial interventions at five NHS hospitals confirmed that none of them 
were currently in routine use (47). After clinical equipoise was confirmed, all eligible 

 
 
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interventions were shortlisted and were prioritised according to their perceived potential to 
impact on SSI rates. The interventions chosen impact different phases of perioperative care 
and as such can be used either in isolation or conjunction with each other and although there 
may potentially be interaction between the interventions (positive or negative) they appear to 
be mechanistically disparate.  
 
(1) 
2% alcoholic chlorhexidine skin prep  
 
Mechanism: A broad-spectrum antiseptic to clean and prepare the skin prior to surgery. 
 
Supplier: Carefusion/BD  
 
Guidelines (as at trial commencement in early 2018):  
• 
WHO recommends alcoholic chlorhexidine-based antiseptic solution for surgical site 
skin preparation in patients undergoing surgical procedures, based on meta-analyses 
of low quality evidence. 
• 
CDC recommends that intraoperative skin preparation should be performed with an 
alcohol-based antiseptic agent unless contraindicated.  
• 
NICE recommends using either an alcohol povidone-iodine or alcoholic chlorhexidine; 
however, recognises that the evidence base remains uncertain. 
 
Evidence base: Published meta-analyses describe 11 randomised controlled trials (RCTs) 
comparing antisepsis with chlorhexidine or povidone-iodine across 6385 patients. 
Chlorhexidine reduced SSI compared with povidone-iodine (pooled RR=0.70; 95% C.I.=0.60-
0.83)(48, 49). This included a large 2010 RCT of 849 mixed speciality patients that showed 
significantly lower SSI in the chlorhexidine alcohol group than in the povidone-iodine group 
(50). However, this trial has been criticised for having a non-pragmatic control group; our 
survey data suggests that few hospitals use 2% alcoholic chlorhexidine routinely in abdominal 
surgery (47). 
 
Guidelines update – NICE guideline Surgical site infections: prevention and treatment [NG125] 
was an update to the previous CG74, and was released in April 2019: 
• 
A thorough review of the available evidence around skin preparation options, including 
a network meta-analysis was performed. To quote directly from the guidelines: “Based 
on the evidence, the committee agreed that an alcohol-based solution of chlorhexidine 
should usually be the first choice when deciding which antiseptic preparation to use. 
However, the quality of the studies was not good enough for the committee to make 
a strong recommendation for the choice of antiseptic preparation.” 
• 
No recommendation was made regarding the optimal strength of chlorhexidine (i.e. 
0.5% versus 2%) – in fact a research recommendation was issued as follows: 
“What is the clinical and cost effectiveness of chlorhexidine in alcohol at different 
concentrations in the prevention of surgical site infection when applied to the skin 
before incision?”. We are likely to provide additional evidence to address this question 
within ROSSINI 2.  
 

 
 
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(2) 
Iodophor-impregnated incise drapes  
 
Please note: In January 2022, following the first interim analysis, arms including intervention 
2 – Iodophor-impregnated incise drape (arms C, E, G and H) were closed to recruitment.  
 
Mechanism: A thin impregnated plastic sheet applied to the prepared skin prior to incision to 
maintain sterility.  
 
Supplier: 3M Infection Prevention 
 
Guidelines (as at trial commencement in early 2018): 
• 
WHO conditionally recommends not to use plastic adhesive incise drapes with or 
without antimicrobial properties, based on lack of evidence of effectiveness from one 
low quality RCT and one very low-quality quasi-RCT. 
• 
CDC makes a weak recommendation that plastic adhesive drapes with or without 
antimicrobial properties are not necessary for the prevention of SSI. 
• 
NICE does not recommend the use of incise drapes due to lack of evidence for 
effectiveness. If an incise drape is required to maintain the integrity of the operative 
site, NICE recommends the use of an iodophor-impregnated drape unless the patient 
has an iodine allergy.  
 
Evidence base: Analysis of a subset of a Cochrane review showed no effect from impregnated 
adhesive drapes on the SSI rate (RR 1.03, 95% CI 0.06-1.66, p=0.89) but this included only 
2 RCTs, only one of which was in abdominal surgery and was nearly 30 years ago (51, 52). A 
more recent non-randomised trial in clean-contaminated abdominal surgery showed 
significant reduction in SSI (12.1% to 3.1%; p=0.0096). Surgeons are known to be keen on 
using the device as it serves to maintain the integrity of the operative field by sticking drape 
edges down. Impregnated incise drapes are part of SSI prevention bundles currently being 
used in major UK and US hospitals (53). 
 
Guidelines update – NICE guideline Surgical site infections: prevention and treatment [NG125] 
was an update to the previous CG74, and was released in April 2019: 
• 
Incise drapes were not re-considered in this guidelines update; no new 
recommendations were made. 
 
 
(3) 
Gentamicin-impregnated sponge  
 
Mechanism: Small absorbable sponges placed into the wound at the time of closure which 
deliver high concentrations of antibiotic locally to kill pathogens present that may go on to 
cause SSI.  
 
Supplier: SERB 
 
Guidelines (as at trial commencement in early 2018): 

 
 
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• 
WHO and CDC do not make a recommendation on the use of gentamicin impregnated 
sponges. 
• 
NICE does not make a recommendation for gentamicin-collagen implants/ sponges in 
abdominal surgery but make a provisional recommendation for their use in cardiac 
surgery. However, NICE express concerns about potential adverse effects of topical 
antibiotics on microbial resistance, and request more evidence from large, pragmatic 
trials with longitudinal assessment of microbial resistance. 
 
Evidence base: A published meta-analysis of 15 RCTs comparing use of the implant/ sponge  
versus placebo or nothing across all types of surgery in 6979 patients (54). Overall the 
implants/ sponges significantly reduced SSI (OR 0.51; 95% CI 0.33-0.77; p=0.001) but the 
majority of trials were in thoracic or pilonidal surgery. A large RCT specifically exploring their 
use in abdominal (colorectal) wounds found an apparent increase in SSI rates in the 
intervention arm, but concerns about the way the implant/ sponge was used have been raised 
(55, 56). A Cochrane review of the intervention is still in analysis but will expect to show 
ongoing equipoise in abdominal surgery (57). 
 
Guidelines update – NICE guideline Surgical site infections: prevention and treatment [NG125] 
was an update to the previous CG74, and was released in April 2019: 
• 
The following important guideline was issued: “Only apply an antiseptic or antibiotic 
to the wound before closure as part of a clinical research trial.” 
• 
The reasoning and rationale behind this statement was summarised as follows: “The 
committee agreed that the evidence was not current or clear enough to make a 
recommendation on the use of topical antiseptics and antibiotics before wound closure. 
The committee also considered concerns about antimicrobial resistance and the 
potential for multidrug resistance, and agreed that without new conclusive evidence, 
use of intraoperative topical antibiotic and antiseptics should be stopped. They agreed 
that this is an important area for further research and recommended that they should 
be considered only in the context of further research to help limit unnecessary use and 
determine their clinical effectiveness. They also developed a research recommendation 
to determine the clinical and cost effectiveness of applying antiseptics and antibiotics 
before wound closure.” 
• 
This research recommendation is directly relevant to, and supportive of, ROSSINI 2 
being undertaken. It was worded thus: “is the application of antiseptics and antibiotics 
in the operative field before wound closure, clinically and cost effective in reducing 
surgical site infection rates?” 
 
 
 
 
 
 
 
 

 
 
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  COVID-19  
On 11th March 2020, the World Health Organization declared the international spread of 
COVID-19 to represent a global pandemic. The unprecedented impact the pandemic had on 
the NHS and wider UK society means that there will be long-reaching or even permanent 
changes to the NHS structures for delivering both patient care and clinical research. As a result 
of these, we had amended some trial processes and pathways in ROSSINI 2 to ensure that 
the trial remains safe and practicable, whilst protecting the scientific and methodological 
integrity of the trial.  
 
These changes had been necessary in the following aspects of the trial: 1) secondary 
objectives; 2) trial entry criteria and 3) patient follow-up pathways.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 AIMS AND OBJECTIVES 
ROSSINI 2 is a multi-arm, multi-stage (MAMS), pragmatic, multicentre, randomised 
controlled trial (RCT) with a 6-month internal pilot. The aims and objectives for the pilot and 
the main trial are defined separately below. 
 
 Internal Pilot (Stage 1) 
 
Aims 
The aims of the internal pilot trial were to assess: 
1) if recruitment to the randomised interventions was feasible 
2) adherence to randomised intervention allocation 
3) if patient follow-up could be completed within protocol-specific timeframes. 
 
The internal pilot aimed to recruit 150 patients across 10 sites. 
 
 
STOP/ GO Criteria 
The following STOP-GO criteria was assessed at 6 months post-start of recruitment 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 stage.  
• 
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 stage. 
 
See Section 3.2: Pilot Stage Summary of Completion (Stage 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 Main Phase III Trial 
 
Primary Objective 
To determine whether several specific in-theatre interventions, used 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. 
 
 
Objectives 
 
Clinical 
• 
Do the intraoperative interventions used alone, or in various combinations reduce the 
overall rate of SSI after abdominal surgery?  
 
• 
Is the efficacy of the intervention/treatment arm dependent upon; 
o degree of wound contamination (clean, clean-contaminated, contaminated, 
dirty)? 
o patient comorbidity (e.g. diabetes, smoking, obesity)?  
o duration of operation? 
o stoma formation? 
o operation approach (laparoscopic-assisted, open)? 
o SARS-CoV-2 virus status on day of surgery (swab positive; negative; not 
tested)? 
o SARS-CoV-2 antibody status on day of surgery (antibody positive; negative; 
not tested)? 
 
• 
Do the intraoperative interventions: 
o have an acceptable safety profile? 
o reduce the rates of wound complications? 
o reduce the rates of mortality? 
 
• 
What is the impact of SARS-CoV-2 virus infection status on overall SSI rate, and in 
those who previously had COVID-19 (proven or suspected), is there a time-dependent 
impact upon overall SSI rates?  
 
 
Economic 
• 
Does the use of the interventions, either alone or in combination: 
o improve health-related QoL? 
o reduce the length of stay in hospital? 
o reduce wound complication related hospital re-admissions? 
o reduce the occurrence of unplanned wound reopening and/ or re-operations? 
o are cost-effective? 
 
 
 
 

 
 
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 Sub Study 
 
 Mechanistic 
• 
Is there microbiological ratification of the clinical findings in terms of pathogenic 
organisms prevented/not prevented by use of the interventions or combinations of 
interventions? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 TRIAL DESIGN AND SETTING 
  Trial Design  
A phase III, multi-arm, multi-stage (MAMS), pragmatic, blinded (patient and outcome 
assessor), multicentre, randomised controlled trial (RCT) with an internal pilot, to evaluate the 
use of several in-theatre interventions to reduce SSI rates in patients undergoing surgery with 
an abdominal incision. Non-factorial superiority design with allocation of various combinations 
of interventions to be used during the same operation. 
 
  Pilot Stage Summary of Completion (Stage 1) 
The Independent Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) held 
a joint meeting on 30th September 2019 to review the internal pilot stage objectives 
and results. They were satisfied with the progress against the predefined progression criteria 
and recommended that ROSSINI 2 continue to the main phase of the trial without the need 
for any major modifications. The NIHR also reviewed trial progress and reports from the 
oversight committees; they confirmed progression to the main phase in October 2019. The 
table below details the success of the internal pilot stage. 
 
STOP / GO 
Criteria 
Aim 
Actual 
Achieved 
Recruitment 
Open 10 sites 
14 
✓ 
Recruit 150 patients 
216 
✓ 
6 of the 10 sites to 
achieve an average 
recruitment of 4 patients 
per month. 
9 of the 14 sites 
opened achieved an 
average of 4 
patients per month. 
✓ 
Adherence 
Investigators’ adherence 
to arm allocation must be 
at least 80%. 
92.8% 
✓ 
Follow-up 
Data submission within 60 
days of randomisation 
should be at least 70%. 
81%-100% 
✓ 
 
  Stage 2 Summary of Completion (First Interim Analysis) 
It was agreed in an extraordinary meeting of the Trial Management Group (TMG), TSC and 
DMC on October 5th 2021 (and subsequently by the Funder) that it would be reasonable to 
bring forward the first interim analysis i.e. sooner than 2357 patients as originally planned. 
This decision was based on observing a slightly higher than expected overall event rate.  
 
On December 15th 2021, the results of the first interim analysis were presented and reviewed 
by the independent DMC. They made the recommendation to drop the intervention arms 
containing Intervention 2, Iodophor-impregnated incise DRAPE. The DMC recommendations 
were discussed by the ROSSINI 2 TMG, independent TSC, Sponsor and Funder at a meeting 

 
 
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on January 7th 2022. Following this meeting, it was agreed that the following arms containing 
Intervention 2, Iodophor-impregnated incise DRAPE, would close to recruitment: 
 
Arm C           DRAPE 
Arm E           SKIN PREP & DRAPE 
Arm G           DRAPE & SPONGE 
Arm H           SKIN PREP & DRAPE & SPONGE 
 
All other aspects such as the primary objective, trial design, trial setting, outcome measures 
and key eligibility criteria remain unchanged. 
 
  Stage 3 of ROSSINI 2 
The health technologies that will be assessed in Stage 3 versus the control arm (standard 
care):  
 
1. 2% alcoholic chlorhexidine skin preparation, versus any other standard skin preparation 
3. Gentamicin-impregnated sponge at closure, versus no sponge 
 
 Trial Setting   
At least 60 NHS hospitals in the UK will participate in ROSSINI 2. 
 
  Identification of participants 
Adults undergoing abdominal surgery will be identified for recruitment in both elective and 
emergency settings. 
• 
In the elective setting patients will be identified via clinics, admission logs, theatre 
booking systems and multidisciplinary team meetings. 
• 
In the emergency setting patients will be identified from the emergency department, 
surgical assessment units and theatre booking systems. 
Embedding surgical trainees, research nurses and consultant surgeons within the site teams 
will maximise the ability to screen for eligible patients. ROSSINI 2 is also participating in 
the NIHR Associate PI scheme – for more details see section 23. 
 
  Patient and public involvement 
This trial has been developed in partnership with patient representatives and service users, 
from the Birmingham Surgical Research Patient Forum. Patient representatives sit on the TMG 
and the TSC providing input into aspects of trial design and delivery, patient-facing 
documentation such as Patient Information Sheets (PIS) and Informed Consent Forms (ICF). 
These individuals will directly represent patients and their views prospectively during all stages 
of the trial. 
All PPI involvement in this trial will be reimbursed according to the INVOLVE guidelines, and 
their participation reported according the GRIPP2 framework (58). 

 
 
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  Sub-studies 
A sub-study is planned in parallel to this MAMS trial to determine if there is microbiological 
ratification of the clinical findings in terms of pathogenic organisms prevented or not 
prevented by use of the interventions or combinations of interventions. This is further detailed 
in Section 20 of this protocol. 
 
  Assessment of Risk 
All clinical trials can be considered to involve an element of risk and in accordance with the 
Birmingham Clinical Trials Unit (BCTU) standard operating procedures this trial has been risk 
assessed to clarify any risks relating uniquely to this trial beyond that associated with usual 
care. A Risk Assessment has been conducted and concluded that this trial corresponds to the 
following categorisation:  
• 
Type A = No higher than the risk of standard medical care 
 
The interventions being assessed in the trial are already being used by a small number of 
surgeons nationally and internationally. They are all commercially available and approved for 
use in the UK. In the absence of level 1 evidence, current behaviours for SSI reduction practice 
are influenced by surgeon experience and hospital policies governing local availability. As a 
pragmatic trial, ROSSINI 2 is designed to have minimal impact upon a patient’s standard 
clinical care and thereby enhance recruitment and adherence to arm allocation, whilst 
maximising follow-up rates. We propose to randomise patients to receive adjunctive 
interventions in addition to standard care in an attempt to decrease their likelihood of 
developing a potentially serious post-operative complication. None of the interventions are 
known to cause harm and none will significantly increase the time of an operation or make it 
more technically difficult. 
 
There are no additional COVID-19 risks from participation in ROSSINI 2. All patients entering 
the trial will have already had a decision made to undergo surgery (in either an elective or 
emergency context) and undergone appropriate local clinical pathways such as swabbing and 
self-isolation to mitigate their overall risks from COVID-19; there are no additional direct risks 
from the trial pathways, interventions or wound assessments if a patient also participates in 
ROSSINI 2. 
 
The only additional patient interactions within this trial are as follows: 
(1) Pre-operative discussions about the trial and provision of PIS  
(2) Consent to participate in the trial 
(3) QoL questionnaire (EQ-5D-5L) at Baseline (pre-op) 
(4) In-theatre randomisation 
(5) Use of the intraoperative intervention(s), unless allocated to control arm 
(6) An in-person (in-patient) wound review by a blinded, trained observer and a QoL 
questionnaire (EQ-5D-5L) at Day 7 (or pre-discharge if sooner). 
(7) Another wound review (either in person or by video consultation, telephone can be 
used as a last resort) by a blinded, trained observer and a QoL questionnaire (EQ-5D-

 
 
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5L) at Day 30, with the intervening period covered by a patient self-reported Wound 
Healing Questionnaire (WHQ). 
(8) Completion of the Resource Use Questionnaire (RUQ) at Day 30. This will give 
information regarding the costs that have been incurred in relation to the patient’s 
wound healing (only applicable in final stage of ROSSINI 2). Sites will be informed 
when this part of the trial is to be implemented. 
(9) If there is an ongoing SSI at day 30, the patient will be requested to complete the EQ-
5D-5L, WHQ and RUQ every 30 days until the infection has resolved. They will not 
need to undergo any further trial related wound assessments beyond Day 30. 
 
We intend to incorporate these into routine care pathways, such as introducing/discussing the 
trial at the pre-operative assessment clinic visit, consenting on the morning of surgery, the 
initial wound assessment whilst an inpatient and the final 30 day wound assessment during 
the standard postoperative follow-up outpatient visit where possible. 
Before opening, all sites will receive trial-specific training, both on the logistical and operational 
aspects of the trial and in the correct use of the various interventions to ensure a standardised 
and optimal method of use. This will mitigate risk of harm through improper application, whilst 
being minimally disruptive to broader clinical practice at the site. It is also essential that any 
staff carrying out a wound assessment must complete the wound assessment training prior 
to conducting any patients’ assessments of their wound. Below is a link to the wound 
assessment training: 
https://bctu-redcap.bham.ac.uk/surveys/?s=DFPM7YMKRJ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 ELIGIBILITY 
  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 to not receive) 
each of them, including combinations thereof. Surgeons must be willing to adhere to arm 
allocation and be trained in a standardised application technique. 
 
  Inclusion Criteria  
• 
Patients undergoing an abdominal operation, these include colorectal, hepatobiliary, 
upper GI, urological, vascular, or gynaecological operations 
• 
Patients undergoing an abdominal operation (open or laparoscopic assisted) with a 
planned incision of at least 5cm 
• 
Patients aged 16 years or older 
• 
Patients able and willing to undergo a wound assessment at day 30-37 after surgery  
• 
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. 
 
  Exclusion Criteria  
• 
Previous laparotomy within 3 months prior to randomisation  
• 
Known to be pregnant or currently breast feeding  
• 
Operations where the wound is not anticipated to be closed primarily  
 
  Notes on Eligibility Criteria  
• 
SARS-COV-2 virus status and antibody status on day of surgery – all patients are 
eligible to enter the trial regardless of positivity, negativity or not tested status. 
• 
Patients with a new or documented allergy/ intolerance to any of the trial interventions 
(chlorhexidine, 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 trial. 
• 
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. 
• 
Purely groin incisions such as inguinal hernia repair or vascular access of the femoral 
vessels do not count as abdominal surgery and are not eligible to enter the trial. 
 
Participants who potentially fulfil the inclusion criteria for this trial must have their eligibility 
confirmed by an appropriately delegated member of the local team with access to and a full 
understanding of the potential participant’s medical history. If eligibility has been assessed 

 
 
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and documented, then the process of obtaining informed consent may be delegated as 
appropriate and as documented on the ROSSINI 2 Site Signature and Delegation Log and if 
the local hospital/ practice allows this as per their own policy. 
Each individual patient should not undergo a second randomisation to ROSSINI 2 within 3 
months post-surgery and until the previously randomised wound has fully healed. 
 
  Co-enrolment 
Participants who have been recruited to another RCT examining an intervention that does not 
share a common biological pathway with impact on the primary outcome measure, are 
permitted to be included within this trial. Sites should contact the ROSSINI 2 Trials Office to 
discuss this prior to co-enrolment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 CONSENT 
It will be the responsibility of the Principal Investigator (or delegate if local site allows) to 
obtain written informed consent for each participant prior to performing any trial related 
procedures. Consent may also be taken by other consultant surgeons or surgical registrars 
(with up-to-date GCP training) as delegated by the local PI and captured on the ROSSINI 2 
Site Signature and Delegation Log. Research nurses and other allied health professionals can 
also obtain consent if local practice allows and this responsibility has been delegated by the 
PI and again, captured on the ROSSINI 2 Site Signature and Delegation Log. 
 
All eligible patients will be approached for recruitment to ROSSINI 2. A Patient Information 
Sheet (PIS) will be provided to facilitate this process. 
Investigators will ensure that they adequately explain: 
• 
That consent is sought for inclusion in a randomised controlled trial 
• 
That the trial will compare different interventions aiming to reduce SSI rates 
• 
That the interventions will be allocated at random and the patient will be blinded to 
the allocation 
• 
What the trial will involve for the participant 
• 
The anticipated benefits and potential risks of taking part in the trial 
• 
The patient will not be offered reimbursement of any expenses occurred as a result 
of participating in ROSSINI 2 
• 
That participation is voluntary and that the participant is free to refuse to take part 
and may withdraw from the trial at any time. 
 
The participant will be given sufficient time to read the PIS and to discuss their participation 
with others outside of the site research team if they wish. The participant has the opportunity 
to ask questions before signing and dating the latest version of the ROSSINI 2 Informed 
Consent Form (ICF). The ICF will be completed using one of the following processes: 
 
• 
Face-to-face (Preferred method) 
The ICF is given to the participant and they will initial, sign and date the ICF. The PI 
or delegate consenting the participant will then sign and date the ICF. Only after the 
PI or delegate has countersigned the ICF is consent considered to be obtained.  
 
• 
By post/ email/ telephone 
The ICF is posted or emailed (and then printed) to the participant, along with the PIS. 
During a telephone discussion between the person consenting and the participant, the 
participant will initial, sign and date the ICF. The PI or delegate will document this in 
the participant’s medical notes. The participant will then post or email the partially 
completed ICF back to the site. The PI or delegate who consented the participant will 
then print (if ICF emailed to site), sign and date the ICF. Only after the PI or delegate 
has countersigned the returned ICF is consent considered to be obtained.  
 

 
 
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When emailing or posting, copies of all correspondence/ letters between the participant (with 
the attached partially completed ICF) and from the person receiving consent (with the fully 
completed ICF attached) are to be printed and stored with the ICF. 
 
A copy of the completed ICF will be given/posted/emailed to the participant, a copy will be 
filed in the medical notes and the original placed in the Investigator Site File (ISF). In addition, 
if the participant has given explicit consent, a copy of the signed ICF will be sent to the 
ROSSINI 2 trials team for review upon request. 
 
Detailed instructions on postal/email consent can be found within your ISF.  
 
The participant must give explicit consent for the regulatory authorities, members of the 
research team and or representatives of the sponsor to be given direct access to the 
participant’s medical records.  
 
Once the participant is entered (randomised) into the trial, the participant’s unique trial 
number (TRIAL ID) will be entered on the ICF and maintained in the ISF.. 
 
Details of the informed consent discussions will be recorded in the participant’s medical notes. 
Stickers can be provided upon request, such discussions (and stickers) will include date of 
discussion, the name of the trial, summary of discussion, version number of the PIS given to 
participant and version number of ICF signed, consent process followed (post, email or face-
to-face) and date consent received. 
 
At each visit (including any follow-up that is conducted remotely), the participant’s willingness 
to continue in the trial will be ascertained and documented in the medical notes. Throughout 
the trial the participant will have the opportunity to ask questions about the trial. Any new 
information that may be relevant to the participant’s continued participation will be provided. 
Where new information becomes available which may affect the participants’ decision to 
continue, participants will be given time to consider and if happy to continue will be re-
consented (if required). Re-consent will be documented in the medical notes. The participant’s 
right to withdraw from the trial will remain.   
 
Electronic copies of the PIS and ICF will be available from the ROSSINI 2 Trial Office and 
will be printed or photocopied onto the headed paper of the local institution. Details of all 
patients approached about the trial will be recorded on the ROSSINI 2 Patient Screening Log 
(held at site) and with the participant’s prior consent, their General Practitioner (GP) will also 
be informed that they are taking part in the trial. 
 
 
 
 
 
 
 

 
 
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 RECRUITMENT, SCREENING AND RANDOMISATION 
  Recruitment 
Patients will be identified as potential participants at the time they are listed for surgery by a 
surgeon, surgical trainee, consultant or nurse. It is envisaged that the majority of patients will 
be screened and recruited in four scenarios:  
1. Surgery outpatient clinics, such as Colorectal, Upper GI, Hepatobiliary/ Pancreatic, 
Renal, Urological, Vascular and Gynaecology – by a Consultant or trainee surgeon 
when the patient is being booked for elective surgery. 
2. Pre-assessment clinic – by a nurse or surgical trainee when the patient is being 
assessed for surgery. 
3. Planned theatre lists – by a Consultant or trainee surgeon once a patient has been 
listed for surgery and arrives in hospital, i.e. at the time of admission for surgery. 
4. In the emergency setting (assessment unit or emergency department) – by a 
Consultant or trainee surgeon when a decision to operate is made. 
 
  Screening 
Potentially eligible patients will be screened and approached for entry into the trial by an 
appropriate member of staff delegated this responsibility on the ROSSINI 2 Site Signature 
and Delegation Log. A ROSSINI 2 Patient Screening Log should be prospectively maintained 
at each site using planned and electronic theatre lists. 
The trial will be discussed with eligible elective patients pre-operatively, either in the 
outpatient clinic at the time of listing for surgery, or in the pre-operative assessment clinic 
where patients come routinely around 7-10 days prior to surgery. 
In the emergency setting, the trial can be discussed with patients at the same time as 
operative consent, once a definitive decision for surgery is made. Written information will be 
provided in the form of a Patient Information Sheet (PIS). In both settings, patients will be 
given as much time as possible to decide whether they wish to take part. 
 
Informed consent for participation in the trial will be obtained pre-operatively and the 
ROSSINI 2 Informed Consent Form will be signed by both elective and emergency patients; 
this will normally be in the same setting where the usual operation consent for the intended 
surgical procedure is also obtained.  
After consent, patient-level demographic data will be collected on the ROSSINI 2 Baseline 
CRF and a baseline health-related, preference-based QoL assessment using the EuroQol EQ-
5D-5L questionnaire should also be completed. 
 
The proportion of participants who temporarily lack capacity to consent to trial recruitment 
due to their disease severity (i.e. undergoing emergency surgery) will be identified from the 
ROSSINI 2 Patient Screening Log and they will not be able to participate in ROSSINI 2 at 
the time.  
 
 
 

 
 
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  Randomisation 
After eligibility has been confirmed and informed consent has been received, the patient can 
be randomised into the trial. It is essential that randomisation into the trial occurs in theatre, 
ideally around the time of induction of anaesthesia on the day of surgery. We have successfully 
developed this method across three other NIHR portfolio multicentre, trainee-led RCTs (1, 18, 
19). This helps maintain concealment of each intervention (blinding) from ward staff, from 
any staff that may conduct the wound review and from the patient. This will also minimise 
bias and attrition from crossover or drop-out. 
 
Randomisation will be via a secure online randomisation system (available at 
https://w3.abdn.ac.uk/hsru/ROSSINI2) or via an automated telephone randomisation system 
(available at 0800 2802 307) both managed by a 3rd party - The Centre for Healthcare 
Randomised Trials (CHaRT) at The Institute of Applied Health Sciences at University of 
Aberdeen. Both systems will be available 24 hours a day, 7 days a week, apart from short 
periods of scheduled maintenance.  
 
A ROSSINI 2 Randomisation Form must be completed in order to randomise a patient. This 
form should be used to collate the necessary information prior to randomisation. All questions 
and data items on the Randomisation Form must be answered before a Trial Number and Trial 
allocation can be given.  
 
 
Randomisation methodology 
Participants will be randomised at the level of the individual in a 2:1 (control:research) ratio 
to either control or one of the intervention arms. Each research arm will specify a single 
intervention or combination of interventions that will be allocated and used during that specific 
operation. These interventions will be applied by the operating team as per the trial protocol 
and each site will be given trial specific training during site set-up to ensure homogeneity.  
 
A minimisation algorithm will be used within the randomisation system to ensure balance in 
the intervention allocation over the following variables: 
• 
Centre 
• 
Urgency (planned, unplanned) 
• 
Predicted contamination (clean, clean-contaminated, contaminated, dirty) 
• 
Stoma (yes – pre-existing, yes – formed during this operation, no)  
 
The contamination level will be predicted by the operating surgeon before a skin incision is 
made, based on available clinical, radiological, endoscopic, biochemical or haematological 
parameters (60, 61):  
• 
Clean – an incision in which no inflammation is encountered in a surgical procedure, 
without a break in sterile technique, and during which the respiratory, alimentary and 
genitourinary tracts are not entered;  
• 
Clean-contaminated – an incision through which the respiratory, alimentary or 
genitourinary tract is entered under controlled conditions but with no contamination 
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• 
Contaminated – an incision undertaken during an operation in which there is a major 
break in sterile technique or gross spillage from the gastrointestinal tract, or an incision 
in which acute, non-purulent inflammation is encountered. Open traumatic wounds 
that are more than 12 to 24 hours old also fall into this category; 
• 
Dirty – an incision undertaken during an operation in which the viscera are perforated 
or when acute inflammation with pus is encountered during the operation (for 
example, emergency surgery for faecal peritonitis), and for traumatic wounds where 
treatment is delayed, and there is faecal contamination or devitalised tissue present. 
 
A ‘random element’ will be included in the minimisation algorithm. Immediately following 
randomisation, a confirmatory, blinded e-mail from CHaRT will be sent to selected members 
of the Research Team. The ROSSINI 2 trial team will receive a randomised allocation 
confirmatory e-mail. At site, only the person who randomised the participant into the trial will 
also receive this unblinded email.  
 
The randomisation allocation, or use of the interventions used within the trial, should not be 
entered on the operation record or patient notes. Instead, stickers are provided in the 
ROSSINI 2 ISF which should be added to the patient notes to explain that the patient is in 
a blinded trial.  
 
Normal local policies for perioperative care, including patient warming, systemic antibiotic 
prophylaxis and venous thromboembolism will be followed, with completion of a standard 
three-stage WHO Surgical Safety Checklist (62). The operation will be carried out as normal, 
with use of the relevant combination of intraoperative interventions (if any) as per the 
randomised allocation. Immediately after the operation, the ROSSINI 2 In-Theatre Form will 
capture the intraoperative details and verify which interventions were utilised and, if there 
were any deviations from the randomised allocation why this occurred. 
 
Investigators will keep a ROSSINI 2 Patient Recruitment and Identification Log which links 
patients with their allocated trial number. Site Staff must maintain this document, which is not 
for submission to the Trials Office. Site Staff will also keep and maintain the anonymised 
ROSSINI 2 Patient Screening Log which will be kept in the ISF, and should be available to 
be sent to the Trials Office on a monthly basis or upon request. The ROSSINI 2 Patient 
Recruitment and Identification Log and ROSSINI 2 Patient Screening Log should be held in 
strict confidence. 
 
  Informing the participant’s GP 
If the participant has agreed, the participant’s GP should be notified that they are in ROSSINI 
2, using the ROSSINI 2 GP Letter. The GP will not be told the patient’s group allocation.  
 
  Blinding 
ROSSINI 2 is an observer-blinded trial; both the patient and outcome assessor will be blinded 
to the intraoperative intervention(s). It is not possible to blind the operating surgeon to the 
intervention allocation. 

 
 
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The following measures will be taken to ensure concealment of the chosen intervention(s) 
(blinding):  
• 
Randomisation in theatre after induction of anaesthesia. 
• 
The intraoperative interventions used will not be documented in the operation note 
or in the patient’s notes. The ROSSINI 2 Trial office will supply participating sites 
with stickers to be used in the patient’s medical notes to confirm that the patient is in 
a clinical trial and who to contact in the event of a medical emergency which 
necessitates unbinding. 
• 
The skin around the closed wound will be wiped clean using a wet sterile towel at the 
end of the procedure to prevent unblinding due to discolouration of the skin. 
• 
Clinical follow-up will be conducted by a trained surgeon (Membership of the Royal 
College of Surgeons level or equivalent) or a trained member of the local research 
team who did not participate in the index procedure or surgery. 
• 
CRFs that contain blinded information should be stored elsewhere to avoid accidental 
unblinding of those carrying out wound assessments. 
 
  Unblinding 
Patients can be unblinded upon request at the end of the trial, which is once the final patient 
has completed all follow-up and the database is locked for final analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 TRIAL INTERVENTIONS 
  Usual care and site requirements 
All patients undergoing an abdominal operation will have their skin prepared using some form 
of antiseptic skin preparation. Only in participants randomised to the trial intervention of 2% 
Alcoholic Chlorhexidine (arms B or F) should this skin preparation be used. For all other 
participants, they should receive the surgeon’s choice of skin preparation as long as this is 
NOT 2% Alcoholic Chlorhexidine. Other commonly used agents include 0.5% chlorhexidine or 
povidone-iodine, in aqueous or alcoholic solution. Concentrations and volumes of preparations 
vary and can be mixed in theatre or used as pre-prepared solutions. No other impregnated 
sponges should be used. 
 
As a pragmatic RCT, ROSSINI 2 will not mandate a rigid set of parallel measures for the 
prevention of SSI as part of usual care in each trial centre, as this would limit wider 
generalisability of the findings. We will, however, stipulate that all sites opening for the trial 
should adhere to a minimum set of policies as per the NICE guidance CG74 (24) on the 
prevention of SSI, monitored using the ROSSINI 2 In-Theatre Form. This includes: 
• 
The monitoring and maintenance of normothermia 
• 
Hair removal, in theatre, immediately before the time of incision, using an electronic 
shaver (if required) 
• 
Administration of empirically selected prophylactic antibiotics 
• 
Use of a standard three-stage WHO Surgical Safety Checklist. 
 
Some sites will undertake additional measures to try and reduce SSI as part of their routine 
patient care. Providing this does not impinge on any of the trial interventions this will be 
allowed to continue, in the interests of pragmatism, and will be captured regularly at a 
surgeon-specific (Trainee) level throughout the trial as we recognise such behaviours and 
measures are likely to evolve throughout the duration of the trial. Participating surgeons at 
sites will be asked to complete an electronic questionnaire (using the REDCap system). This 
questionnaire will collect information on any changes to practice or new interventions 
employed during the course of the trial which may impact on the baseline SSI rates. 
 
Before opening, all sites will receive trial-specific training on the logistical and operational 
aspects of the trial. All investigators will undergo a training and certification process that 
includes: 
1. Watching videos outlining proper use of study interventions 
2. Training on the correct use of the interventions by a member of the TMG or the local 
PI 
3. Access to standardised ‘training cards’ for use in theatre as an aide memoire for the 
application of the intervention technique 
 
This will ensure the correct use of the various interventions to ensure a standardised and 
optimal method of use.  
 
 

 
 
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  Intraoperative interventions and comparators 
Intervention 1: 2.0% Alcoholic Chlorhexidine Skin Prep (BD Infection 
Prevention) 
This intervention describes the preparation of the intact skin incision site immediately prior to 
incision, using chlorhexidine gluconate (CHG) in an alcohol-based solution, providing durable 
sterilisation of the surgical field. Pre-prepared applicators will be available for use in this trial 
(ChloraPrep™ sticks, 2% CHG with 70% isopropyl alcohol, BD Infection Prevention).  
To prepare the applicator: 
• 
The ChloraPrep stick must be ‘activated’ by depressing the trigger. 
• 
Ensure that the 2% alc. CHG is leeching into the sponge at the end of the ChloraPrep 
applicator. 
To apply the 2% alc. CHG: 
• 
Begin by cleaning the umbilicus using the provided sticks, saturated in the 2% alc. 
CHG solution 
• 
Use the ChloraPrep applicator to begin preparing the surgical field, starting directly 
over the planned incision site 
• 
Use a backwards and forwards or circular motion for 30-60 seconds over the surgical 
incision site before moving outwards towards the limits of the surgical field 
• 
Use of a second applicator may be necessary in field sizes greater than 30cm x 30cm, 
if the operating surgeon deems this appropriate 
• 
The prepared field must be outwith that of the operating field insight. 
Before applying sterile drapes around the operating field: 
• 
Manage any pooling by drying with a single, sterile towel or gauze  
• 
Allow the 2% alc. CHG solution to dry for at least 2-3 minutes until the shiny surface 
changes to a matt effect on the prepared skin. 
 
If further extension of the prepared field, or re-sterilisation of the operating field is required 
for any reason during the procedure, then a further ChloraPrep may be used.  
 
Comparator 1: All patients undergoing an abdominal operation will have their skin prepared 
using some form of antiseptic skin preparation. Only in participants randomised to the trial 
intervention of 2% Alcoholic Chlorhexidine (arms B or F) should this skin preparation be used. 
For all other participants, they should receive the surgeon’s choice of skin preparation as long 
as this is NOT 2% Alcoholic Chlorhexidine. Other commonly used agents include 0.5% 
chlorhexidine or povidone-iodine, in aqueous or alcoholic solution. Concentrations and 
volumes of preparations vary and can be mixed in theatre or used as pre-prepared solutions. 
The ROSSINI 2 In-Theatre Form will collect which skin prep was used in the control arm and 
ensure compliance to the randomised allocation.  
 
  
 
 
 
 

 
 
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Please note: In January 2022, following the first interim analysis, arms including 
intervention 2 – Iodophor-impregnated incise drape (arms C, E, G and H) were closed to 
recruitment. 
 
Intervention 2: Iodophor Antimicrobial Incise Drape (3M Infection Prevention) 
This intervention describes the application of a single Iodophor Antimicrobial Incise Drape to 
be applied topically onto the prepared and draped surgical field by sterile, gloved members of 
the surgical team before the surgical incision is performed. Only after the skin preparation 
solution has dried completely can the incise drape be applied.  
To prepare the drape for application: 
• 
Remove the outer packaging 
• 
Remove the paper overwrap  
• 
Hold the drape with the printing on the handle facing up  
• 
Separate the printed handle from the white handle  
To apply the drape to the operating field, a two-person application is optimum, with one 
person standing on each side of the operating table: 
• 
Person one holds the printed handle  
• 
Person two pulls the white edged liner away from the printed handle 
• 
Both persons should place their hands on the outer corners of the drape to maintain 
slight tension on the drape and keep the area wrinkle free  
• 
Gently unfold the drape over the operating field ensuring the limits of the drape are 
outwith the draped area of skin 
• 
Stop unfolding the drape once the clear film is found on the white edge of the drape 
• 
Smooth out any wrinkles with a sterile towel or gloved hand and ensure contact 
between the skin and the drape throughout 
• 
Remove the remainder of the liner and the printed handle.  
 
At the end of the procedure when the skin has been closed the incise drape should be removed 
at 180 degrees, back on itself and away from the operating field. As the drape is adherent, 
care must be taken to gently remove the drape form the patient’s skin without causing 
abrasion or injury. Specific training for the use of this intervention can be found in a separate 
appendix. 
 
Comparator 2: In the control arm, no incise drape (Iodine impregnated, or non-iodine 
impregnated) will be used. 
 
Intervention 3: Gentamicin-impregnated sponge (SERB)  
This intervention describes the implantation of Gentamicin-impregnated collagen sponges at 
the time of fascial closure. Each sponge (5 by 20 cm) contains 280mg of collagen and 130mg 
of gentamicin. The sponges gradually degrade and the gentamicin solution permeates into 
surrounding tissues to create a high local antimicrobial concentration within the surgical 
wound.  
To prepare the sponges for implantation: 
• 
Remove outer packaging  
• 
The sponge can be cut to size through the sterile packaging whilst dry 

 
 
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• 
Ensure all gloved hands or instruments are free of blood before handling the sponge 
• 
Ensure the area to be treated is dry 
To implant the sponges at the surgical site: 
• 
Fascial closure will be completed according the surgeon’s local practice  
• 
One or two sponges should be inserted anteriorly to the fascia, along the full length 
of the incision 
• 
Place light pressure to the sponge until adhesion to the fascia is achieved 
• 
This should occur immediately before closure of the surgical skin wound  
 
Comparator 3: In the control arm, no sponge should be used and closure of the subcutaneous 
tissues and skin should be performed according the surgeon’s standard practice. 
 
  Contraindications  
An investigator must confirm the patient’s eligibility to be randomised to each of the 
interventions at the time of randomisation. If a patient is not able to receive a trial 
intervention, they will still be randomised to the remaining arm(s) and the reasons for this will 
be recorded on ROSSINI 2 Randomisation Form and collated by the ROSSINI 2 Trial Office. 
 
If a patient has a new or documented allergy or intolerance to Chlorhexidine AND Gentamicin 
or Collagen, or end stage renal failure, then the patient is not eligible to participate in 
ROSSINI 2. 
 
Specific contraindications to each included intervention are: 
Intervention 1: 2.0% Alcoholic Chlorhexidine Skin Prep (BD Infection Prevention) 
• 
Do not use on broken skin or mucous membranes 
• 
Do not use if the patient has a known sensitivity to Chlorhexidine. 
 
 Intervention 2: Iodophor Antimicrobial Incise Drape (3M Infection Prevention) 
• 
Do not use if the patient has a known sensitivity to iodine. 
• 
Do not attempt to defibrillate through the drape. 
 
Intervention 3: Gentamicin-impregnated sponge (SERB)  
The peak permitted serum-gentamicin concentration for a patient with normal renal function 
is 3-5mg/litre (63). 
 
• 
Do not use in end-stage renal failure (per local hospital prescribing policy) or severe 
acute kidney injury (KDIGO stage 2/3, or acute requirement for renal replacement 
therapy). 
• 
Do not use if the patient has a known sensitivity to gentamicin. 
• 
Do not use if the patient is on concurrent gentamicin therapy via another route (a 
single dose of gentamicin at induction is permissible) 
• 
Do not use if the patient has a known sensitivity to proteinaceous implants. 
• 
Bovine collagen comes from cows and is the most common source of collagen in 
medical supplements and implants. After harvesting the cattle for their meat, the cow 

 
 
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hides (skins) are removed and then treated to extract their collagen protein. All cellular 
material and DNA is removed. Patients will be informed of this via the PIS and should 
they not be willing to be randomised to receive this intervention, they will not be able 
to enter the trial.  
 
  Accountability and Compliance Procedures 
It is important to ensure that patients receive the allocated interventions and that they are 
applied with high fidelity during their operation to ensure the internal validity and 
reproducibility of the trial findings. Compliance to the arm allocation will be monitored using 
two mechanisms: 
 
 (1) The intervention(s) used in theatre will be collected on the ROSSINI 2 In-Theatre Form. 
 (2) The number and resupply of trial interventions will be monitored by the ROSSINI 2 Trials 
Team and assessed against expected levels whenever a reordering request is required, or 
delayed.  
 
The ROSSINI 2 Trials Team will actively monitor adherence to arm allocations, exclusions of 
patients from arms of randomisation and resupply of trial interventions. None of the 
interventions are ‘complex’ to adopt, or involve a learning curve in their use, safety or 
effectiveness, so high fidelity monitoring of steps for implementation is not required. However, 
to ensure that all interventions are used in a homogenous and reproducible manner by all 
surgeons and sites, standardised training materials have been created. 
 
  Cessation of Treatment/ Continuation after the Trial 
The 2.0% Alcoholic Chlorhexidine skin preparation intervention is applied intraoperatively. The 
Gentamicin-impregnated sponges are left in situ postoperatively. 
Patients who undergo re-laparotomy, wound exploration or explantation of the sponge will 
continue to be followed up to 30 days from the index procedure. The number of reoperation 
events will be collected as part of the ROSSINI 2 Return to Theatre Form (only report 
incidents that occur within 30 days post-surgery). 
If any trial intervention is withdrawn from the trial for a safety reason, randomised patients 
would be alerted immediately and appropriate, reparative safety measures will be taken. At 
this point, the patient would be asked whether they would like to continue to be part of the 
trial follow-up. 
 
  Treatment Supply and Storage 
 
Treatment supplies 
The manufacturer of each product will be responsible for the free provision of trial 
interventions to the ROSSINI 2 Trials Team. An initial supply of the interventions will be 
delivered to each site prior to site opening. It will then be the responsibility of the ROSSINI 
2 Trials Team to arrange for resupply, delivery and redistribution. The process for this will be 
explained during the Site Initiation Visit. 

 
 
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The trial interventions (or box in which they are held) will be marked with a label “For 
ROSSINI 2 Trial Use Only”. The labels will be provided in the ISF and are available from the 
ROSSINI 2 Trial Office should sites require additional supplies. 
 
The industry partners supporting the provision of interventions for the ROSSINI 2 Trial are: 
Intervention 1: 2.0% Alcoholic Chlorhexidine Skin Prep 
(BD Infection Prevention) 
  
Intervention 2: Iodophor Antimicrobial Incise Drapes 
(3M Infection Prevention) 
 
Intervention 3: Gentamicin-impregnated /sponges 
(SERB)  
 
 
Packaging, Labelling and Storage 
All interventions will be stored in a secure, clean, dry place free from damp at room 
temperature and within the supplied sterile packaging. No specific special requirements are 
required above the standard storage conditions of theatre products and refrigeration will not 
be necessary. Any excess intervention material will be disposed of in the hospital’s standard 
clinical waste bins as per local hospital protocol. Interventions must only be used for patients 
within the trial, randomised to the arm in question. Any centres using interventions outside 
the trial setting may be cautioned, asked to withdraw from the trial or be asked for 
reimbursement.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 OUTCOME MEASURES AND TRIAL PROCEDURES 
  Primary Outcome  
 
Definition 
The primary outcome measure is the SSI rate up to 30 days after surgery as defined according 
to the 2017 Centers for Disease Control (CDC) and Prevention criteria. Whilst several systems 
exist to define SSI, the internationally recognised CDC definitions are the current gold standard 
for SSI assessment and have been used in a number of multicentre randomised trials. 
 
The following CDC definition will be used in ROSSINI 2 to identify deep incisional or 
superficial incisional SSIs:  
The interventions in the trial act locally on the wound and its surroundings to reduce 
contamination, both exogenous and endogenous, and thereby prevent the development of 
postoperative wound infection. Surgical site infection in ROSSINI 2 encompasses both 
superficial and deep incisional wound infections. In practice, a deep incisional infection will 
manifest alongside a superficial one and can be viewed as a more severe subset of the latter. 
We will not seek to differentiate between deep and superficial SSI as our interventions seek 
to prevent both. The trial does not include organ space infections as an outcome measure; 
this is a rare complication when compared with superficial/deep infections and importantly, 
organ space infections are not likely to be affected (positively or negatively) by the 
interventions chosen for ROSSINI 2. We recognise the subjective component to SSI 
assessment and have sought to minimise this by applying centralised training and 
1. The infection must occur within 30-days of the index operation  
AND  
2. The infection must involve the skin, subcutaneous, muscular or fascial layers of the 
incision  
AND  
3. The patient must have at least one of the following:  
• 
Purulent drainage from the incision  
OR 
• 
Wound opened spontaneously or deliberately by a clinician 
o AND the patient has at least one of: pain or tenderness; localised swelling; 
erythema or heat; fever (>38°C).  
OR 
• 
Organisms are cultured from a culture taken from the wound using an aseptic 
technique  
OR  
• 
Diagnosis of SSI by a clinician or on imaging 

 
 
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accreditation of the assessors using our previously developed online e-learning module. This 
approach was used successfully in the ROSSINI 1 trial (1). 
 
  Secondary Outcomes 
• 
30-day postoperative mortality rate (POMR). 
• 
30-day postoperative wound complication rate (Clavien-Dindo classification). 
• 
Wound or intervention only related 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 Quality of Life (QoL EQ-5D-5L) at Baseline, Day 7 (or discharge if 
sooner) and Day 30. 
• 
Cost effectiveness (Resource Use Questionnaire; RUQ). 
 
 
Definitions and Timings 
 
30-day postoperative mortality rate 
The 30-day postoperative mortality rate (POMR) is determined as death of a patient within 
the first 30 postoperative days, with day of surgery taken as day 0. POMR has been highlighted 
as a key performance indicator by the Lancet Commission on Global Surgery and 
recommended for use in all international clinical trials in surgery (67). In the ROSSINI 1 trial, 
with a similar participant inclusion criteria the POMR was 2.6% (1). 
 
 
30-day postoperative wound complication rate 
The 30-day postoperative wound complication rate is determined as the highest level Clavien-
Dindo grade complication measured in the first 30 postoperative days, with day of surgery 
taken as day 0. Any deviation from the normal postoperative course that has an adverse effect 
on the patient’s wound and is not either a treatment failure or sequel, is a complication. The 
Clavien-Dindo classification determines the severity of a complication based on the therapeutic 
consequence of that complication (68). This has been validated internationally across health 
settings with high reproducibility and low interrater variability.  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Classification Definition 
Grade 1 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological 
interventions. 
Acceptable 
therapeutic 
regimens 
are: 
drugs 
as 
antiemetics, antipyretics, analgesics, diuretics and electrolytes and 
physiotherapy. This grade also includes wound infections opened at the 
bedside. 
Grade 2 
Requiring pharmacological treatment with drugs other than such allowed 
for grade I complications. Blood transfusions and total parenteral 
nutrition are also included. 
Grade 3 
Requiring surgical, endoscopic or radiological intervention. 
Grade 4 
Life-threatening complication (including Central Nervous System 
complications) requiring critical care management. 
Grade 5 
Death of a patient. 
Table 1. Clavien-Dindo classification of postoperative complications 
 
 
Health-related, preference-based quality of life 
QoL will be assessed using the widely validated EuroQol EQ-5D-5L questionnaire at baseline 
(preoperative), as an inpatient at Day 7 or at discharge if sooner and another at Day 30 
mirroring the timings of blinded wound assessment. If the patient has an ongoing SSI 30 days 
post-operatively, then the EQ-5D-5L questionnaire will be completed every 30 days until the 
wound has fully healed (e.g. Day 60, Day 90, Day 120 etc.). 
 
 
Cost-effectiveness 
Cost effectiveness will be assessed using the RUQ to collect patient-level health resource 
usage both in primary and secondary care; reported in QALYs. This has been previously piloted 
in the ROSSINI 1 trial (1). The RUQ will be utilised in the last stage of ROSSINI 2 and Sites 
will be notified when to implement this.  
 
 
 
 
 

 
 
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  Schedule of Assessments  
Visit 
Pre-operative 
(Elective and 
emergency surgery) 
 
At 
surgery 
Day 7 
wound review 
 
(To be completed as an inpatient 
on Day 7, or discharge if sooner) 
 
+2 days 
Day 30 
wound review 
 
(To be completed as an 
outpatient, between 
Day 30-37) 
 
Ongoing SSI 
 
(every 30 days 
until resolution) 
Eligibility confirmation 
X 
 
 
 
 
Patient Information Sheet provided 
X 
 
 
 
 
Written Informed Consent+ 
X 
X 
X 
X 
X 
Baseline  
(BASELINE CRF & CONTACT CRF) 
X 
 
 
 
 
Randomisation 
(RANDOMISATION CRF) 
 
X 
 
 
 
Operation 
(IN-THEATRE CRF) 
 
X 
 
 
 
Blinded Wound Assessment / review 
(WOUND ASSESSMENT CRFs) 
 
 
X* 
X** 
 
Readmissions for surgery 
(RETURN TO THEATRE CRF) 
 
X++ 
 
Serious Adverse Event Reporting  
(SAE CRF) 
 
X 
 
Questionnaires:  
Quality of Life Questionnaire (EQ-5D-5L) 
X^ 
X 
X 
X 
Wound Healing Questionnaire (WHQ) 
 
 
 
X 
X 
Resource Use Questionnaire (RUQ)$ 
 
 
 
X 
X 
+ It is important to also reaffirm consent at each trial visit. 
* Wound assessment data collected here should be applicable and relevant between Day 0 (day of surgery) to Day 7 Wound Assessment (or up to discharge). 
** Wound assessment data collected here should be applicable and relevant between Day 7 (first wound assessment) to Day 30 Wound Assessment (second wound assessment). Data should not be 
duplicated over forms. If no previous wound assessment has occurred, then data collected should be from Day 0 to Day 30. 
++ Only to be completed if patient is required to return to theatre (within 30 days post-surgery) for any reason. 
^ Quality of Life at Baseline should be completed after Consent but before Surgery. 
$ RUQ will only be collected on those participants in the final stage of the trial. Sites will be notified when to implement this.

 
 
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  Trial Follow-Up Assessments 
Participant retention will be maximised by minimising deviation from the usual postoperative 
patient pathway. If an in-person wound assessment is not possible, the protocol does allow 
for a wound assessment to be conducted using real-time telemedicine remote video 
consultation. Telephone follow up assessments and data captured via routinely collected data 
documented in the patients’ medical records, of the wound can be used as a last resort.   
 
 
 Pre-discharge/ Day 7 Wound Review 
To be performed at day 7 (assessment window: days 5 to 9), or within one day of discharge 
(if sooner), by a blinded, in-person wound assessor. The wound will be assessed for an 
infection according to the CDC SSI criteria, since the day of surgery. 
The assessment will be undertaken by a member of the research team or clinical investigator 
who has been trained in the diagnosis of wound infections and who is blinded to the 
randomised allocation. These delegates must be tasked this role, have undergone the wound 
assessment training (https://bctu-redcap.bham.ac.uk/surveys/?s=DFPM7YMKRJ) and have 
signed the ROSSINI 2 Site Signature and Delegation Log prior to carrying out any wound 
assessments. 
It is recommended that at this time point, patients should be given a Patient Reminder Card 
(PRC) to inform them of their upcoming Day 30 Wound Assessment. Please refer to section 
8.5 for more information on PRCs. 
As part of this wound assessment, the Wound Assessment (Day 7) CRF will be completed.  
 
 
Day 30 Wound Review 
To be performed 30 days post-operation (assessment window days 30-37; with day 0 being 
the day of surgery) by a blinded, in-person wound assessor. If a direct face-to-face wound 
assessment is not possible for whatever reason, this wound assessment is to be conducted 
using real-time telemedicine remote video consultation. If neither of these follow-up methods 
are possible, telephone follow up assessments and data captured via routinely collected data 
documented in the patients’ medical records, of the wound can be used as a last resort. The 
wound will be assessed for an infection according to the CDC SSI criteria and since the 
previous wound assessment. If no previous wound assessment has occurred (at Day 7), then 
data collected should be from Day 0 to Day 30. Data should not be duplicated over CRFs. 
 
This assessment will be undertaken by a member of the research team or clinical investigator 
who has been trained in the diagnosis of wound infections and who is blinded to the 
randomised allocation and it may be performed at the hospital where they underwent their 
primary operation, or at an alternative local research clinic as required. In many cases this 
may mirror standard postoperative care in patients undergoing abdominal surgery. As part of 
this wound assessment, the Wound Assessment (Day 30) CRF will be completed.  
 
To maximise the fidelity of the follow-up period between discharge and the Day 30 Wound 
Assessment, a patient-reported Wound Healing Questionnaire (WHQ) will be completed at the 
Day 30 follow-up visit in conjunction with the researcher’s wound assessment. The WHQ is a 
single patient and observer measure for post-discharge SSI assessment. It contains 18 data 

 
 
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points that are easily understood and completed with the support of a healthcare professional 
(64). It has been developed as part of an NIHR HTA-funded (12/200/04) mixed-methods 
feasibility study of wound dressing strategies to reduce SSI (65, 66). Patients may also be 
asked to complete the RUQ, this will give information regarding the costs that have been 
incurred in relation to the patient’s wound. The RUQ will only be collected on those participants 
in the final stage of the trial. Sites will be notified when to implement this. 
 
Participants will be made aware of the requirement for a 30-day follow-up assessment before 
informed consent is taken. In exceptional circumstances where a patient becomes unable or 
unwilling to attend a follow-up appointment in person or via telemedicine video consultation 
at 30-days, every effort will be made to complete the WHQ (and any other questionnaires) by 
telephone as a last resort. Whilst the number of patients this will apply to is expected to be 
minimal, the effect of questionnaire-based follow-up only will be assessed in sensitivity 
analysis. 
 
 
Wound assessments 
The wound will be assessed by a blinded, experienced individual, trained in this role who has 
signed the ROSSINI 2 Site Signature and Delegation Log. Outcome assessments will be 
undertaken by individuals who were not involved in the operation and thus blinded to the trial 
arm allocated. We anticipate that this group will include local surgical trainees, research nurses 
and nurse specialists, all of whom will be specifically trained and accredited as being capable 
of diagnosing an SSI, using a pre-existing online training tool (https://bctu-
redcap.bham.ac.uk/surveys/?s=DFPM7YMKRJ). This system will reduce inter-observer 
variability and make an inherently subjective endpoint as reliable and reproducible as possible.  
 
 
Follow-up beyond the Primary Trial Window 
In patients who have an ongoing wound infection at 30-days postoperatively, these patients 
will continue to have ongoing active follow-up every 30 days until resolution. This will require: 
 
• 
Completion of the EQ-5D-5L questionnaire 
• 
Completion of the WHQ 
• 
Completion of a RUQ (only in the final stage of the trial) 
 
These questionnaires at these time points will be completed with the patient via the telephone 
or sent via the post by staff at site. 
 
This group of patients will include less than 5% of those with an index SSI event, but will 
account for over 50% of healthcare utility, cost and impact on quality of life. A protracted 
follow-up period will allow ROSSINI 2 to assess the incremental impact of the most ‘severe’ 
SSI. 
 
 
 
 
 

 
 
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  Patient Reminder Cards  
The purpose of these cards is to inform patients of their upcoming Day 30 Wound Assessment. 
Informing a patient in advance of their future assessment should prevent patient drop-out 
and withdrawals.  
 
  Withdrawal / Change of Status 
Informed consent is defined as the process of learning the key facts about a clinical trial before 
deciding whether or not to participate. It is a continuous and dynamic process and participants 
should be asked about their ongoing willingness to continue participation. 
 
Participants should be aware at the beginning that they can freely withdraw (discontinue 
participation) from the trial (or part of) at any time.   
 
Participants found to be ineligible post randomisation should be followed up according to all 
trial processes and will still have their data analysed unless they explicitly change their level 
of participation.  
 
Participants are able to withdraw (cease participation) from the following aspects of the 
ROSSINI 2 trial: 
 
• 
Surgery  
• 
Follow Up (Wound Assessments at Day 7 & Day 30) 
• 
Patient reported Questionnaires  
• 
Ongoing SSI Follow Up (QoL, WHQ & RUQ) 
• 
All of the above 
 
The changes in levels of participation within the trial are categorised in the following ways: 
 
• 
No trial related follow-up: The participant does not wish to attend trial visits in 
accordance with the schedule of assessments, but is willing to be followed up at 
standard clinic visits and if applicable using any central UK NHS bodies for long-term 
outcomes (i.e., the participant has agreed that data can be collected at standard clinic 
visits and used in the trial analysis, including data collected as part of long-term 
outcomes). 
• 
No further data collection: The participant is not willing to be followed up in any 
way for the purposes of the trial AND does not wish for any further data to be collected 
(i.e., only data collected prior to any changes of levels in participation can be used in 
the trial analysis). 
 
The details of withdrawal (date of withdrawal, reason and type of withdrawal) should be 
clearly documented in the source documents and on the Change of Status CRF, the ROSSINI 
2 trial office should also be informed immediately. 
 
 

 
 
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 ADVERSE EVENT REPORTING 
9.1.   Definitions 
Adverse Event 
 
AE 
Any untoward medical occurrence in a participant 
participating in the trial which does not necessarily 
have a causal relationship with the intervention 
received.   
Related Event 
 
RE 
An event which resulted from the administration of 
any of the research interventions. 
Serious Adverse Event 
 
SAE 
An untoward occurrence that:  
Results in death  
Is life-threatening*  
Requires hospitalisation or prolongation of existing 
hospitalisation 
Results in persistent or significant disability or 
incapacity 
Consists of a congenital anomaly/ birth defect 
Or is otherwise considered medically significant by 
the Investigator** 
Unexpected Event 
 
UE 
The type of event that is not listed in the protocol as 
an expected occurrence. 
Related and Unexpected 
Serious Adverse Event 
 
N/A 
A SAE that meets both the definition of a Related and 
Unexpected Event. 
* The term life-threatening is defined as diseases or conditions where the likelihood of death 
is high unless the course of the disease is interrupted.  
** Medical events that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the participant or may require intervention to prevent one 
of the other outcomes listed in the definitions above. 
 
  Adverse Event recording - General 
The recording and reporting of Adverse Events (AEs) will be in accordance with the UK Policy 
Framework for Health and Social Care Research, the Principles of GCP as set out in the UK 
Statutory Instrument (2004/1031; and subsequent amendments) and the requirements of the 
Health Research Authority (HRA). 
 
Definitions of different types of AEs are listed in the table above. 
 
It is routine practice to record AEs in the participant's medical notes and it is also 
recommended that this includes the documentation of the assessment of severity and 
seriousness and also of causality (relatedness) in relation to the intervention(s) in accordance 
with the protocol.  
 

 
 
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Adverse Event (AE) reporting in ROSSINI 2 
The reporting period for AEs in ROSSINI 2 will be from the day of surgery (when the 
interventions were administered) until the end of trial follow-up (30 days later).  
AEs are commonly encountered in participants undergoing colorectal, hepatobiliary, upper GI, 
urological, vascular, or gynaecology operations. As the safety profiles for this trial population 
and the interventions used in this trial are well characterised, and will not affect the safety of 
participants, a strategy of targeted reporting of AEs will be used. 
Only (expected) AEs that are infection and wound complication related will be recorded on 
the relevant CRFs as part of the outcome measures for this trial, these include: 
 
Infection related: 
• 
Pain or tenderness at the incision site 
• 
Localised swelling 
• 
Redness at the incision site 
• 
Heat at the incision site 
• 
Fever 
 
Complication related: 
• 
Granuloma 
• 
Haematoma 
• 
Seroma 
• 
Dehiscence 
 
 
Serious Adverse Event (SAE) reporting in ROSSINI 2 
For all SAEs, the PI or delegate must do one of the following: 
 
1. Record safety reporting - exempt SAEs in the medical notes but not report them 
to the trials office on an SAE form (or any other CRFs) as per Section 9.2.2.1.  
 
2. Report SAEs to the trial office in a non-expedited manner. This can only be done 
for the pre-defined subset of SAEs as per Section 9.2.2.2. 
 
3. Report SAEs to the trial office in an expedited manner (within 24 hours of the site 
research team becoming aware of the event). All SAEs not covered by the above 
categories must be reported as per Section 9.2.2.3.  
 
Note: When an SAE occurs at the same hospital at which the participant is receiving trial 
intervention or is being followed up for trial purposes, processes must be in place to make the 
trial team at the hospital aware of any SAEs, regardless of which department first becomes 
aware of the event, in an expedited manner. 
 
 
Serious Adverse Events not requiring reporting to the Trial Office  
At whatever time they occur during an individual’s participation, from randomisation to the 
end of participant follow-up, the following are not considered to be critical to evaluations of 
the safety of the trial: 

 
 
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o SAEs that are related to a pre-existing condition 
o SAEs that are related to symptoms or progression of the participant’s disease 
o Pre-planned hospitalisations. 
 
All events which meet the definition of serious must be recorded in the participant notes, 
including the causality and severity, throughout the participant’s time on trial, including follow-
up, but for trial purposes these events do not require reporting on the SAE Form. Such events 
are “safety reporting exempt”.  
 
 
Serious Adverse Events requiring non-expedited reporting to the Trial 
Office  
Where the safety profile is well established, the causal relationship between the participant’s 
underlying condition or surgery, and the SAE, may be known. That is, such events are 
protocol-defined as “expected”.  
 
Such events should still be reported in the patient’s medical records and on the relevant CRFs, 
but do not require expedited reporting on an SAE Form (immediately on the site becoming 
aware of the event) since the assessment of expectedness for the specified events has been 
pre-defined; 
o Death (unrelated to the trial/ intervention(s)) 
o Interventions (either within theatre, radiology department or on the ward) to drain 
wound infections 
o Anastomotic leak 
o Intra-peritoneal collections (with or without intervention) 
o Thrombo-embolic events 
o Infections not related to the wound (eg. pneumonia, urinary tract infections) 
o Cardiac or central nervous complications 
o Paralytic ileus  
o Prolonged hospital stay as a result of wound infections 
o Wound complications 
o Surgical site infections 
 
 
Serious Adverse Events requiring expedited reporting to the Trial Office  
The following SAEs (that are related to the use of each intervention (or the control)) should 
always be recorded and reported (within 24 hours) to the BCTU Trials Office as a SAE, on the 
In-Theatre Form and SAE Form: 
 
• 
Death (related to the trial/ intervention(s)) 
• 
Skin reactions 
• 
Allergic reactions 
• 
Combustion 
 
Participants may suffer from other complications from their surgery or their underlying 
condition but if these are unrelated to their wound and/or the intervention(s), they do not 
need to be reported on a SAE Form even if they meet the usual criteria of an SAE. 

 
 
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If a participant has experienced any of these prior to receiving any of the intervention(s) then 
they do not need to be reported as an SAE. 
 
Any other SAEs that are related and unexpected would require expedited reporting to the trial 
office. 
 
  SAE Reporting Process  
On becoming aware that a participant has experienced an SAE which requires reporting on an 
SAE Form, the PI (or delegate) should report the SAE to their own Trust in accordance with 
local practice and to the ROSSINI 2 Trial Office at BCTU.  
 
To report an SAE to the Trial Office at BCTU, the PI or delegate(s) must complete, date and 
sign the ROSSINI 2 SAE Form. The completed form together with any other relevant, 
appropriately anonymised, data should be faxed or emailed to the BCTU trials team using the 
number listed below as soon as possible and no later than 24 hours after first becoming 
aware of the event: 
 
 
 
 
 
 
 
Where an SAE Form has been completed by someone other than the PI, the original SAE Form 
will be required to be countersigned by the PI to confirm agreement with the causality and 
severity assessments. 
 
On receipt of an SAE Form, the ROSSINI 2 Trials Team will allocate each SAE a unique 
reference number and notify the site via email as proof of receipt. The site and the ROSSINI 
2 Trials Team should ensure that the SAE reference number is quoted on all correspondence 
and follow-up reports regarding the SAE and filed with the SAE Form in the ISF. 
 
If the site has not received confirmation of receipt of the SAE from the ROSSINI 2 Trials 
Team or if the SAE has not been assigned a unique SAE identification number within 1 working 
day, the site should contact the ROSSINI 2 Trials Team. 
 
  Assessment of causality of an SAE 
When completing the SAE Form, the PI (or delegate) will be asked to define the nature of the 
seriousness and causality (relatedness, see Table 3) of the event. 
 
In defining the causality, the PI (or delegate) must consider if any concomitant events or 
medications may have contributed to the event and, where this is so, these events or 
medications should be reported on the SAE form. It is not necessary to report concomitant 
events or medications which did not contribute to the event.  
To report an SAE, fax or email the SAE form to: 
 
0121 415 8871 or email to ROSSINI2@trials.bham.ac.uk 

 
 
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As per Table 3 all events considered to be ‘possibly’, ‘probably’, or ‘definitely’ related to the 
intervention will be reported by the trial office as ‘related’; all events considered at site to be 
‘unlikely’ or ‘unrelated’ to the intervention will be reported by the trials office as ‘unrelated’. 
The same categorisation should be used when describing AEs and protocol-exempt SAEs in 
the source data. 
 
 
Category 
Definition 
Causality 
Definitely 
There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out 
Related 
Probably 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship. 
However, the influence of other factors may have contributed 
to the event (e.g. the patient’s clinical condition, other 
concomitant events or medication) 
Unlikely 
There is little evidence to suggest there is a causal relationship; 
there is another reasonable explanation for the event (e.g. the 
patient’s clinical condition, other concomitant events or 
medication) 
Unrelated 
Not 
related 
There is no evidence of any causal relationship 
Table 3. Categories of causality 
 
On receipt of an SAE Form, the Trial Office will forward it, with the unique reference number, 
to the CI (or delegate), who will independently* review the causality of the SAE. An SAE 
judged by the PI or CI (or delegate) to have a reasonable causal relationship with the trial 
intervention will be regarded as a related SAE. The severity and causality assessment given 
by the PI will not be downgraded by the CI (or delegate). If the CI (or delegate) disagrees 
with the PI’s causality assessment, the opinion of both parties will be documented, and where 
the event requires further reporting, both opinions will be provided with the report.  
 
*Where the CI is also the reporting PI an independent clinical causality review will be 
performed. 
 
 
Assessment of expectedness of an SAE by the CI  
The CI (or delegate) will also assess all related SAEs for expectedness with reference to the 
criteria in Table 4 below. 
 
Category 
Definition 
Expected 
An adverse event that is consistent with known information about the trial 
related procedures or that is clearly defined in the relevant safety 
information. 
Unexpected 
An adverse event that is not consistent with known information about the 
trial related procedures. 
Table 4. Categories of expectedness 

 
 
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If the event is unexpected (i.e., it is not defined in the protocol as an expected event) it will 
be classified as a related and unexpected SAE.  
 
The CI will undertake review of all SAEs and may request further information from the clinical 
team at site for any given event(s) to assist in this.  
 
 
Provision of SAE follow-up information 
Following reporting of an SAE for a participant, the participant should be followed up until 
resolution or stabilisation of the event. Follow-up information should be provided using the 
SAE reference number provided by the Trial Office. Once the SAE has been resolved, all critical 
follow-up information has been received and the paperwork is complete, a copy of the final 
version of the completed SAE form must be submitted to the Trial Office and the original kept 
in the ISF. 
 
 
Monitoring pregnancies for potential Serious Adverse Events 
There is not an identified risk of congenital anomalies or birth defects in the offspring of 
participants as a result of their participation in the trial. We have also excluded pregnancies 
and breastfeeding individuals from the trial and for these reasons, pregnancies will not be 
monitored for any potential SAEs. 
 
  Reporting SAEs to third parties 
The independent DMC may review any SAEs at their meetings. 
 
The Trial Office will submit a progress report to the REC annually starting 12 months after the 
date of the favourable opinion was given. An electronic copy should be emailed to the REC 
within 30 days of the end of the reporting period. 
 
The Trial Office will report all events categorised as Unexpected and Related SAEs to the 
Research Ethics Committee (REC) and UoB Research Governance Team (RGT) within 15 days 
of being notified. 
 
Becton Dickinson UK LTD, 3M United Kingdom PLC and SERB will be notified of any SAEs that 
occur in participants treated with their product alone or in combination. 
These will be forwarded on a regular basis (monthly or quarterly) and sent as a list of events. 
No patient identifiable information will be given to the company.  
 
  Emergency Unblinding 
Emergency unblinding will only be permitted for urgent clinical/ medical reasons (e.g. severe 
allergy) or patient safety issues. This can be done by all investigators involved in participant 
care by contacting the Trial Office Monday to Friday, 9:00 to 17:00 UK time, except for bank 
holidays, government guided closures and University of Birmingham (UoB) closed days.  
 

 
 
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In case of an out-of-hours emergency, the named person who randomised and/or operating 
surgeon should be contacted for the allocation and the ROSSINI 2 Trials Office should be 
notified at the earliest available opportunity. 
If it becomes necessary to unblind, where possible, members of the site research team will 
remain blinded, subject to clinical need. 
 
Unblinded participants will continue to have outcome assessment up to 30 days 
postoperatively and the impact of this will be examined in a sensitivity analysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 DATA HANDLING AND RECORD KEEPING 
    Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. In order to allow for the accurate reconstruction of 
the trial and clinical management of the subject, source data are kept as part of the 
participants’ medical notes (paper or electronic) and will be accessible and maintained at site.   
 
Typically, the data provided on all CRFs should routinely be recorded in the patient’s medical 
notes, when this is not being conducted then data collected for the purpose of ROSSINI 2 
can be recorded on the paper CRFs. Data should then be transcribed to REDCap and the data 
on paper will be considered the source data, and should subsequently be filed in the ISF.  
 
    Data handling during paper phase of ROSSINI 2 
For the paper phase of ROSSINI 2, sites recorded data on paper CRFs, data clarifications 
were raised on paper DCFs and then the originals were sent to the ROSSINI 2 trials office. 
The copies were kept at the local site. The trials office were responsible for transcribing the 
data from the originals into the electronic CRF. The electronic CRF is held on a secure REDCap 
database at Birmingham Clinical Trials Unit.  
 
    Data handling during electronic phase of ROSSINI 2 
For the electronic phase of ROSSINI 2, all data and any data clarifications will be entered 
onto the secure eCRF directly by staff at sites. Data management will then continue as 
described in section 10.6. 
At no point in the trial will there be simultaneous input of data to a form by both the ROSSINI 
2 Trial Team and staff at site.  
 
    Case Report Form (CRF) Completion 
Case Report Form (CRF) definitions:  
Baseline: 
Basic demographic data including date of birth, NHS number, sex, BMI, comorbidity etc 
Contact Form: 
Contains contact information including the patient’s name 
Randomisation Form: 
Contains all details required to randomise a patient including pre-operative predictions. 
In-Theatre Form: 
 
Theatre data including interventions used and operative details etc  
Wound Assessment (Day 7 or before discharge): 
 

 
 
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First blinded wound review  
Wound Assessment (Day 30): 
Second blinded wound review  
Return To Theatre Form: 
Contains all details including reasons why patient has to return to theatre. 
EQ-ED-5L: 
 
Quality of Life Questionnaire, to be completely at Baseline, Day 7, Day 30 and Ongoing SSI if 
applicable. 
Wound Healing Questionnaire: 
The intervening period (Day 7-30) covered by a patient self-reported Wound Healing 
Questionnaire (WHQ) to be completed at Day 30 and Ongoing SSI if applicable. 
Resource Use Questionnaire: 
Health resource usage will only be collected on those participants in the final stage of the trial. 
Once implemented, to be completely at Day 30 and Ongoing SSI if applicable. 
Change of Status Form: 
Details the change of a patient’s status, reason for change and level of data collected.  
SAE Form: 
Details of an event that meets the definition of an SAE and requires expedited reporting. 
 
Data reported on each CRF will be consistent with the source data and any discrepancies will 
be explained. All missing and ambiguous data will be queried. Only delegated staff on the 
ROSSINI 2 Site Signature and Delegation Log and those trained in GCP are able to complete 
the CRFs. CRF completion guidelines will be sent to all sites and will include guidance on:  
 
• 
CRF completion and corrections   
• 
Date format and partial dates  
• 
Rounding conventions (if applicable) 
• 
Trial-specific interpretation of data fields 
• 
Which forms to complete and when 
• 
What to do in certain scenarios, for example when a subject withdraws from the trial 
• 
Missing/incomplete/unknown data 
• 
Completing SAE forms and reporting SAEs  
• 
Protocol and GCP non-compliances 
 
In all cases it remains the responsibility of the site’s PI (or delegate) to ensure that the CRF 
has been completed correctly and that the data are accurate. This will be evidenced by the 
signature of the site’s PI (or delegate), on the paper CRF (per form) during the paper phase 
and/or on the eCRF (per patient) during the electronic phase of the trial. 
 
Only CRFs specified in the protocol must be used. 

 
 
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    Participant completed Questionnaires  
Participants will be asked to complete a health - related QoL questionnaire (EQ-5D-5L) at 
Baseline (after consent, before surgery), Day 7 (or discharge if sooner), Day 30 and only if 
applicable, every 30 days until the present wound infection has fully healed. Participants will 
also be asked to complete the Wound Healing Questionnaire (WHQ) at Day 30 and if 
applicable, every 30 days until the patient’s wound infection has fully healed. These 
questionnaires can be completed as an inpatient, in clinic or on the ward with the support of 
the research nurse or trainee surgeon, if necessary. 
 
If a patient has been discharged, and has provided consent, research staff at site may 
telephone a participant and complete all questionnaires by proxy.   
 
    Data Management 
Processes will be employed to facilitate the accuracy and completeness of the data included 
in the final report. These processes will be detailed in the trial specific data management plan. 
Coding and validation will be agreed between the trial manager, statistician and programmer 
and the trial database will be signed off once the implementation of these has been assured. 
 
Entries on the paper CRFs should ideally be made in ball point pen, ideally in black ink and 
must be legible. Any errors should be crossed out with a single stroke, the correction inserted 
and the change initialled and dated. The ROSSINI 2 Trial Office will check incoming paper 
CRFs, or data entered in REDCap, for compliance with the protocol, data consistency, missing 
data and timing.  
 
Data reported on each CRF (paper or electronic) should be consistent with the source 
document or the discrepancies should be explained. If information is not known, this must be 
clearly indicated on the CRF. Completed CRFs will be reviewed by the ROSSINI 2 trial office 
for completeness and all missing and ambiguous data will be queried using a Data Clarification 
system in line with the ROSSINI 2 Data Management Plan and will focus on data required 
for trial outcome analysis and safety reporting. Queries (in REDCap) and Data Clarification 
Forms (DCFs) will be generated on a regular basis by ROSSINI 2 trial office staff and sent 
to the site for clarification. 
In all cases, it remains the responsibility of the Principal Investigator (or delegate) to ensure 
that the CRF has been completed correctly and that the data are accurate. PIs (or delegates) 
will be required to sign off on all patients. 
 
The electronic CRFs will be held on a REDCap database at the University of Birmingham. 
 
CRF formatting may be amended and the versions updated by the ROSSINI 2 trial office, as 
appropriate, throughout the duration of the trial. Whilst this may not constitute a protocol 
amendment, new versions of the CRFs must be implemented by participating sites 
immediately on receipt. 
 
 

 
 
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    Data Security 
UoB has policies in place, which are designed to protect the security, accuracy, integrity and 
confidentiality of Personal Data. The trial will be registered with the Data Protection Officer at 
UoB and will hold data in accordance with the Data Protection Act (2018 and subsequent 
amendments).  
 
The Trial Office has arrangements in place for the secure storage and processing of the trial 
data which comply with UoB policies.  
 
The Trial Database System incorporates the following security countermeasures: 
• 
Physical security measures: restricted access to the building, supervised onsite repairs 
and storages of back-up tapes/disks are stored in a fire-proof safe. 
• 
Logical measures for access control and privilege management: including restricted 
accessibility, access controlled servers, separate storage of non-identifiable data etc.   
• 
Network security measures: including site firewalls, antivirus software and separate 
secure network protected hosting etc. 
• 
System Management: the System shall be developed by the BCTU Programming Team 
and will be implemented and maintained by the BCTU Programming Team.   
• 
System Design: the system shall comprise of a database and a data entry application 
with firewalls, restricted access, encryption and role based security controls.   
• 
Operational Processes: the data will be processed and stored within the Trial Centre 
(University of Birmingham).   
• 
System Audit: The System shall benefit from the following internal/external audit 
arrangements: 
o Internal audit of the system  
o An annual IT risk assessment  
• 
Data Protection Registration: The University of Birmingham has Data Protection 
Registration to cover the purposes of analysis and for the classes of data requested. 
The University’s Data Protection Registration number is Z6195856. 
 
    Archiving 
Archiving will be authorised by the ROSSINI 2 Trial office on behalf of the Sponsor following 
submission of the end of trial report. It is the responsibility of the PI to ensure all essential 
trial documentation and source documents (e.g. signed ICFs, Investigator Site Files, 
participants’ hospital notes, copies of CRFs etc.) at their site are securely retained for at least 
10 years. No documents will be destroyed without prior approval from the Trials Office on 
behalf of the sponsor.  
 
 
 
 
 
 
 

 
 
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 QUALITY CONTROL AND QUALITY ASSURANCE 
    Site Set-up and Initiation 
The CI is required to sign a UoB CI agreement to document the expectations of both parties. 
The UoB CI agreement document must be completed prior to participation. The CI is required 
to sign a Clinical Trials Task Delegation Log which documents the agreements between the 
CI and BCTU. In addition, all local PIs will be asked to sign the necessary agreements and 
contracts including a Site Signature and Delegation log between the PI and the CTU and 
supply a current CV and GCP certificate to BCTU. All members of the site research team are 
required to sign the ROSSINI 2 Site Signature and Delegation Log, which details which tasks 
have been delegated to them by the PI. The Site Signature and Delegation Log should be kept 
up to date. It is the PI’s responsibility to inform the Trial Office of any changes in the site 
research team. 
 
Prior to commencing recruitment, each recruiting site will undergo a process of initiation either 
by a meeting or a tele/video-conference, at which key members of the site research team are 
required to attend. Key members must have completed GCP training. The Site Initiations at 
all sites will cover aspects of the trial design, protocol procedures, adverse event reporting, 
collection and reporting of data and record keeping.  Where possible, site teams from across 
different eligible surgical specialties (e.g. Colorectal, Gynaecological, Hepatobiliary surgery) 
will all be invited to this initiation visit to build efficiencies within the site team. Sites will also 
be provided with an ISF containing essential documentation, instructions, and other 
documentation required for the conduct of the trial. The BCTU trials team must be informed 
immediately of any change in the site research team. 
 
Before opening, all sites will receive trial-specific training, both on the logistical and operational 
aspects of the trial and in the correct use of the various interventions to ensure a standardised 
and optimal method of use. This will mitigate risk of harm through improper application, whilst 
being minimal disruptive to broader clinical practice at the site. 
 
    Monitoring  
Due to the nature of ROSSINI 2 there is a need for monitoring to ensure safety of 
participants, clinician acceptability, adherence to arm allocation, clinician effectiveness of each 
arm and the credibility of the data. Monitoring will be performed in accordance with the 
ROSSINI 2 Monitoring Plan by visiting the trial site(s) (‘on-site monitoring’) which gives the 
benefit of access to source documents. Centralised monitoring techniques will also be 
employed. Findings generated from monitoring will be shared with local R&D departments.  
 
 Onsite Monitoring 
Onsite Monitoring will be carried out as required following trial specific risk assessment and 
as documented in the monitoring plan. Any monitoring activities will be reported to the trials 
team and any issues noted will be followed up to resolution. Additional on-site monitoring 
visits may be triggered, for example by poor CRF return, poor data quality, low or high SAE 
reporting rates, excessive number of participant withdrawals or deviations.  If a monitoring 

 
 
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visit is required the Trials team will contact the site to arrange a date for the proposed visit 
and will provide the site with written confirmation. Investigators will allow the ROSSINI 2 
trial staff access to source documents as requested. The monitoring will be conducted by 
members of BCTU. 
 
 Central Monitoring  
Trials staff will be in regular contact with the site research team to check on progress and 
address any queries that they may have. Trials staff will check incoming ICFs (when 
requested) and CRFs for compliance with the protocol, data consistency, missing data and 
timing. Sites will be sent DCFs or queries in REDCap requesting missing data or clarification 
of inconsistencies or discrepancies at a frequency and intensity determined by the Data 
Management plan.   
 
    Audit and Inspection 
The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory 
inspection(s) at their site, providing direct access to source data/documents. The investigator 
will comply with these visits and any required follow up. Sites are also requested to notify 
BCTU of any relevant inspections or local audits.   
 
    Notification of Protocol Non-Compliances and Serious Breaches 
 General Definitions of a Non-compliance  
 
A Protocol Non-Compliance is defined as any:  
❖ violation of GCP or a violation in accordance with the ROSSINI 2 Protocol or relevant 
trial specific guidelines. 
❖ deviation or departure from an approved protocol.  
 
A Continuing Non-compliance is a series of more than one noncompliant event, in 
reasonably close proximity that indicates the need for evaluation of the methods and 
systems used to ensure accurate and reliable data collection as part of the trial. Continuing 
non-compliance need not involve a sequence of similar events if the events, taken as a 
whole, indicate that examination of the methods and systems used is warranted. This can 
also include, in extreme circumstances, the need for evaluation of the methods and 
systems used to protect human subjects. 
 
A combination of continuing non-compliances may result in a serious breach. 
 
 General Definitions of a Serious Breach  
A Serious Breach is a noncompliant event that has or had the potential to:  
❖ impact rights, welfare or safety of present, past or future subject(s),  
❖ increase the risks and/or decrease the benefit for research subjects(s), or 
❖ compromise the integrity of the trial data  
 

 
 
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The sponsor is responsible for notifying the REC of any serious breach of the conditions and 
principles of GCP in connection with that trial or the protocol relating to that trial. Sites are 
therefore requested to notify the Trials Office of any suspected trial-related serious breach of 
GCP and/or the trial protocol. Where the Trials Office is investigating whether or not a serious 
breach has occurred sites are also requested to cooperate with the Trials Office in providing 
sufficient information to report the breach to the REC where required and in undertaking any 
corrective and/or preventive action.   
 
Sites may be suspended from further recruitment in the event of serious and persistent non-
compliance with the protocol and/or GCP, and/or poor recruitment. Any major problems 
identified during monitoring may be reported to the Trial Management Group, Trial Steering 
Committee, and the REC. This includes reporting serious breaches of GCP and/or the trial 
protocol to the REC. A copy is sent to the University of Birmingham Clinical Research 
Compliance Team at the time of reporting to the REC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 END OF TRIAL DEFINITION 
The end of trial will be six months after the last data capture. This will allow sufficient time 
for the completion of protocol procedures, data collection, data input and data cleaning in 
preparation for the database to be locked for the clinical data analysis. The Trials Office will 
notify the main REC and RGT that the trial has ended and a summary of the clinical trial report 
will be provided within 12 months of the end of trial. 
Where the trial has terminated early, the Trials Office will inform the REC within 15 days of 
the end of trial.  
 
A copy of the end of trial notification as well as the summary report will also be sent to the 
University of Birmingham Research Governance Team at the time these will be sent to the 
REC.  
 
 STATISTICAL CONSIDERATIONS  
    Sample Size 
 Justification of sample size 
The justification for the sample size is based on evidence from high-quality prospective 
registries, international audits and randomised controlled trials using the CDC definition of 
SSI. 
 
Author 
Year 
Type 
Type of 
surgery 
n= 
SSI 
rate 
(%) 
Smith et al. 
2004 
Prospective registry 
Colorectal 
176 
26.0 
Blumetti et al. 
2007 
Prospective registry 
Colorectal 
428 
25.0 
Howard et al. 
2010 
Prospective registry  
Colorectal 
122 
25.3 
Daneman et al. 
2010 
National surveillance programme Colorectal 
25086 
22.2 
Serra-Aracil et 
al. 
2011 
Prospective registry 
Colorectal 
611 
24.9 
VINCat 
2014 
National surveillance programme Colorectal 
13661 
20.7 
 
Total 
40084 
24.0 
 
Table 5. Summary of SSI rates from high-quality prospective registries 
 
In an unweighted pooled analysis of high-quality prospective registries; n=40084 (Table 5), 
the SSI rate was 24.0%. In the GlobalSurg 2 international multicentre prospective audit of 
SSI across 76 countries, patient-level outcomes were recorded after 15830 abdominal 

 
 
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operations. The overall SSI rate varied significantly across HDI (human development index) 
tertiles but when limited to High HDI countries such as the UK (n=8470), the overall SSI rate 
after open abdominal surgery was 18%.  
 
Author 
Year 
Intervention assessed 
in RCT 
Type of 
surgery 
n= 
Control 
arm SSI 
rate (%) 
Suzuki et al. 
2003 
Nasal decontamination 
Digestive  
395 
22.0 
Itani et al. 
2006 
Prophylactic antibiotics 
Colorectal 
1002 
26.2 
Meyhoff et al. 
2009 
High concentration oxygen Abdominal 
1386 
20.1 
Anthony et al. 
2011 
Bundle of interventions 
Colorectal 
211 
24.0 
Pinkney et al. 
2013 
Wound edge protector 
Abdominal 
760 
25.3 
Tanaka et al. 
2015 
Wound lavage 
Liver 
193 
21.9 
 
Total 
3947 
23.3 
 
Table 6. Summary of SSI rates from control arm of high-quality RCTs 
 
An unweighted pooled analysis of high quality RCTs in which SSI was the primary endpoint 
(Table 6) and is thus formally assessed in a protocolised fashion with in-person post-discharge 
review, provided a mean SSI rate of 23.3% (n=3947).  
 
For ROSSINI 2 a conservative control group SSI rate of 15% was selected to account for the 
increasing use of minimal access operative techniques across the study population. 
 
 Cohort enrichment 
We recognise that certain patient groups eligible to enter the trial (e.g. clean surgery) will 
carry a lower baseline SSI rate, and if these groups are over-represented, there is the potential 
for the trial to become underpowered. This issue must however be counterbalanced with the 
deliberately pragmatic nature of the trial and the requirement to produce generalizable results 
that are relevant and can be applied to real-world clinical practice.  
 
‘Cohort enrichment’ will provide confidence that ROSSINI 2 will produce useful and robust 
results. We propose to monitor (through the TSC) two groups of patients to ensure that pre-
set proportions are met throughout the trial, giving the DMC the ability to modify these 
proportions if needed, according to the control arm SSI rate, which will be made available to 
them by the independent DMC at each of the pre-planned interim analysis points: 
• 
Emergency operations: it is known that emergency abdominal surgery carries a 
significantly higher SSI rate, both due to the pathological indications for emergency 

 
 
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surgery causing increased levels of contamination and the worse physiological status 
of the patients themselves. We will stipulate that a minimum of 20% of the overall 
cohort entering the trial should undergo emergency surgery. It is a challenge to recruit 
patients within the acute setting, but our research network of trainees has previously 
demonstrated its ability to access and recruit such patients; in our ROSSINI 1 trial the 
proportion of patients undergoing emergency abdominal surgery successfully recruited 
into the trial was 22%. 
• 
Laparoscopic (minimal access) operations: the trial needs to include minimally invasive 
surgery to ensure it is relevant to modern abdominal surgical practice. The current 
proportion of abdominal surgery performed laparoscopically varies depending on the 
speciality, but current UK data suggests 40% of colorectal resections (70), 25% of 
liver resections (71) and 25% of upper gastrointestinal resections (72) are performed 
laparoscopically. We have included operations starting laparoscopically, providing 
there will be a specimen extraction site of at least 5cm, as is the case for most 
resectional surgery. This minimum wound size stipulation is necessary both to allow 
application of all interventions under investigation, some of which are inserted into the 
open wound, and also to maintain the baseline event rate as above by excluding more 
minor operations such as laparoscopic cholecystectomy or appendicectomy. Reported 
SSI rates after major resectional laparoscopic operations eligible for the trial are 
reported 30-45% lower than the corresponding open surgery operations (29, 30, 73-
75). For these reasons we will stipulate that a minimum of 50% of the overall cohort 
should be undergoing open surgery.  
 
 Sample size calculation – overall summary 
The sample size is based on an assumption that the SSI rate in the control arm will be 15%. 
For all research arms, we are targeting a reduction in this rate to 10%, with a loss to follow-
up of 4% of patients. The trial is planned in 4 stages, one pilot stage, two interim analyses, 
and one final analysis. At each interim analysis, we have planned that at least two research 
arms will not randomise any further patients. Therefore, the maximum number of research 
arms in the trial will reduce from 7 to at most 5 after the first interim analysis, and 
subsequently to a maximum of 3 after the second interim analysis. The first interim analysis 
is planned once approximately 2350 patients have joined the trial and the second interim 
analysis is planned when approximately 4630 patients have been recruited. Given this design, 
it is anticipated that approximately 6610 patients will be entered into the trial.  
 
This total recruitment number has been calculated under the assumption that only two 
research arms are dropped at each interim analysis. The calculation takes into account the 
number of formal comparisons being analysed throughout the trial, because large numbers of 
comparisons can lead to spurious statistically significant results. If more than 2 arms are 
dropped at an interim analysis, then the trial as a whole will require fewer comparisons and 
thus the total recruitment number may need to be modified. Any recalculation of the sample 
size (due to greater than planned numbers of arms being dropped from the trial) will only be 
carried out after the second interim analysis, when the number of arms progressing to final 
analysis is known.    
 

 
 
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Overall sample size 
Approximately 6610 patients across all arms and stages 
Total number of stages 
4 stages (including pilot stage) 
Total number of arms 
8 arms at the beginning (1 control, 7 research arms) 
At most, 6 arms after interim analysis 1 (1 control, at most 5 
research) 
At most, 4 arms after interim analysis 2 (1 control, at most 3 
research) 
Allocation ratio 
2:1 = Control : Research 
Primary Outcome Measure 
Proportion of patients reporting Surgical Site Infections up to 30 
days after surgery.  
Control arm SSI rate at 30 
days after surgery 
15% 
Targeted Research arm SSI 
rate at 30 days after surgery 
10% (33.3% relative reduction) 
Lost to follow-up or patients 
without data 
4% 
Table 7. Overall sample size and design assumptions 
 
 Sample size calculation – design assumptions  
Projected recruitment: The knowledge gained from running ROSSINI 1 has been invaluable in 
our recruitment predictions. We know that 50 to 160 eligible operations will be undertaken 
each month at each site, with all specialities included. It is likely that the trial will recruit 
primarily from general surgery, which still leaves 30 to 100 operations per month. In ROSSINI 
1, one site randomised 5 patients in a single day. Our recruitment target of 4-5 patients per 
month per site represents a conservative estimate. 
 
Allocation ratio: During Stage 1 and Stage 2, the allocation ratio is A : B : C : D : E : F : G : H 
= 2 : 1 : 1 : 1 : 1 : 1 : 1 : 1. Arm A is a comparator for all arms, so each research arm will be 
compared with the control arm A individually (pairwise comparison). When arms are dropped 
following an interim analysis, the allocation ratio will remain 2:1 for control:research. We 
propose to randomise more patients to the control arm than research arms to maximise the 
power for each pairwise comparison.  
 
Significance level, power, family-wise error rate: No formal comparison between research and 
control arms will be performed at the end of the pilot stage. The one-sided significance level 
and power, for stages 2, 3 and 4 are 0.40, 0.14, 0.005 and 94%, 94%, 91% respectively 
(Table 8). These values are used to ensure that there is an overall family wise error rate of 
0.025 one-sided and overall (pairwise) power of 85%. The family wise error is defined as the 
probability of rejecting at least one true null hypothesis at the end of the trial. Statistical 
literature (59-61) for MAMS trial designs advises using first stage significance level between 
0.2 and 0.5 one-sided. This is a similar approach to the significance levels used for phase II 
trials. Loss to follow-up: It is assumed that 4% of patients will be lost to follow-up or the 
primary outcome evaluation will be missing, e.g. surgery not done. This is based on the data 

 
 
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from ROSSINI 1 trial (25), where the primary outcome measure was missing for 25/760, 
3.3% patients (14/760 lost to follow-up, and 11/760 laparotomy not done).  
 
Time to decision: We anticipate that the time to decision about continuing or stopping 
recruitment to the research arms will be approximately 4 months: For the first and second 
interim analyses, once the target number of patients is recruited, it is expected that around 4 
months will pass until the decision time regarding stopping and/or continuing research arm(s). 
This is to allow for 30 day FU, CRFs to be completed and posted to the coordinating Clinical 
Trials Unit, data to be entered, interim analysis to be performed, DMC and TSC meetings to 
be held. The DMC will make a recommendation and TSC will make the final decision regarding 
stopping and/or continuing recruitment to research arms. This decision will take into account 
both the efficacy, adherence to the treatment and any other relevant factors. 
 
Table 8. Sample Size Details 
* across all arms. This includes patient who will be recruited by the time of each stage analyses completion 
+ note that this excludes arms dropped at stages 2 and 3, and includes patients recruited in stage 3 
** recruitment will be completed around 38 months from the start of trial recruitment 
 
Pilot sample size: It was planned for the pilot stage to last 6 months and to recruit 
approximately 150 patients. Formal sample size calculation is not applicable for the pilot stage.  
Please see section 3.2 for the Pilot Stage Summary of Completion. 
 
Stages 2, 3 and 4 sample size: it is anticipated approximately 402, 854, and 1887 control arm 
patients will be included in Stage 2, 3 and 4 analyses respectively. Based on the recruitment 
rate assumption, it is expected that by the time of decision regarding arms in Stage 2, 3 and 
4 analyses, 523, 1173 and 1966 control arm patients will have been recruited due to the (a) 
4 months’ time period between the randomisation of the last patient needed for the analysis 
and time of decision – see above “time to decision” (b) patients who were lost to follow-up. 
At the end of the trial, it is anticipated that approximately 6610 patients will be randomised 
across all arms. This includes patients from arms which will close to further randomisations at 
Stages 2 and 3, and arms which will continue until the end of the trial. The sample size may 
be recalculated after the second interim analysis if more than the minimum 2 arms are 
dropped at either of the interim analyses.  
 
Stage 
Cumulative 
sample size* 
Patients 
recruited 
in all 
active 
arms 
Control/ 
Research 
arm 
patients 
for 
analysis 
Cumulative 
time from 
randomisation 
to analysis 
completion 
Number 
of active 
arms 
Targets for 
1-sided 
significance 
level 
[Power] 
Pairwise 1-
sided 
significance 
level [FWER] 
Pairwise 
power 
1 
Pilot 
150 
No sample 
size target 
6 months 
8 
N/A 
N/A 
N/A 
2 
2357 
2357 
402/201 
19 months 
8 
0.40 [94%] 
0.004 [0.0254] 
85% 
3 
4632 
4108 
854/427 
27 months 
6 
0.14 [94%] 
4 
Approx. 6610 
4915+ 
1887/944 
33 months** 
4 
0.005 [91%] 

 
 
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Recruitment and trial duration: Based on the initial recruitment assumption, it was expected 
that recruitment would be completed around 3.1 years from the start of trial recruitment and 
final results known at 41 months (which excludes the 6 months trial set-up stage). However, 
due to the impact of the COVID-19 pandemic, these timelines have been extended.  
 
Design characteristics: This design achieves one-sided family-wise error rate of 0.0253, using 
a one-sided significance level of 0.004 and power of 85% for each pairwise comparison. 
Sample size was calculated using Stata version 14.2 commands –nstagebinopt- and -
nstagebin-. 
 
    Analysis of Outcome Measures  
A separate Statistical Analysis Plan (SAP) will be produced and will provide a more 
comprehensive description of the planned statistical analyses. A brief outline of these analyses 
is given below. The primary comparison groups will be composed of those randomised to the 
trial interventions either alone or in combination versus those in the control arm. In the first 
`instance, all analyses will be based on the intention to treat principle, i.e. all participants will 
be analysed in the treatment group to which they were randomised irrespective of compliance 
or other protocol deviation. For all major outcome measures, summary statistics and 
differences between groups, e.g. relative risks and absolutely differences will be presented, 
with 95% confidence intervals and p-values also given.  Analysis of the primary outcomes will 
be adjusted for the minimisation variables listed in section 6.3.1 (except centre as many 
centres are expected to randomise only a few patients) where possible. We are assessing 
each research arm as ‘independent research arms’ because we think there may be important 
interactions between the components of research arms carrying multiple interventions.  An 
adjustment for multiple comparisons has already been made by increasing the proportion of 
patients in the control arm, and selecting a 0.025 FWER.  
 
Each end-of-stage analysis will be carried out when a sufficient number of patients have 
contributed data to the primary outcome analysis (see section 13.1.4). Each research arm will 
be compared to the control arm only. After each analysis, the DMC will review confidential 
data and will make a recommendation to the Trial Steering Committee, who will make the 
final decision about continuing and/or stopping recruitment to the research arms. The 
comparison between the arms will be evaluated with the absolute difference in proportion of 
patients reporting Surgical Site Infection (SSI) at 30 days (difference: control arm – research 
arm). An adjusted risk difference and an adjusted relative risk and the associated 95% 
confidence interval will be estimated from a Poisson model with robust error variances. The 
percentage of patients who have no data on the primary outcome measure (for example 
because they were lost to follow-up, or were randomised but did not have surgery) will be 
monitored closely and is accounted for in the sample size calculation.  
 
 Primary Outcome Measure 
The primary outcome measure of the trial is the presence/absence of surgical site infection 
(SSI) within 30 days of randomisation. This outcome is a binary outcome (i.e. yes/no). The 
number and percentage of participants experiencing SSI within 30 days of randomisation will 

 
 
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be reported for each research group and the control group. An adjusted absolute risk 
difference and adjusted relative risk ratio, and the associated 95% confidence intervals, will 
be estimated from a Poisson model with robust error variances. The p-value from the 
associated test statistic will be produced and used to determine statistical significance. 
 
  Secondary Outcome Measures 
The secondary outcomes for the trial include continuous, categorical and time-to-event data 
items. 
 
Time to Event Outcomes (e.g. length of hospital stay, mortality) 
Time to event outcomes will be compared between treatment groups using standard survival 
analysis methods. Kaplan-Meier survival curves will be constructed for visual presentation of 
time-to-event comparisons. Cox proportional hazard models will be fitted to obtain adjusted 
treatment effects which will be expressed as hazard ratios with 95% confidence intervals. 
 
Categorical Outcomes (e.g. SSI at discharge) 
For binary secondary outcomes, the number and percentage of participants reporting each 
outcome will be reported by treatment group. An adjusted risk difference and adjusted relative 
risk, and the associated 95% confidence intervals, will be estimated from a Poisson model 
with robust error variances. The p-value from the associated chi-squared test will be produced 
and used to determine statistical significance. 
 
Continuous Outcomes (e.g EQ-5D-5L) 
Continuous outcomes will be reported using means and standard deviations. The EQ-5D-5L 
will be compared between treatment groups with adjusted mean differences and 95% 
confidence intervals estimated using linear regression models. Change in EQ-5D-5L score from 
baseline may also be modelled. 
 
 Exploratory Interaction Analysis 
Interaction analyses will be limited to the same variables used in the minimisation algorithm 
for the primary outcome only. These will be examined by including an intervention group by 
subgroup interaction parameter in the regression model, and will be presented alongside the 
effect estimate and 95% confidence interval within subgroups. The results of subgroup 
analyses will be treated with caution and will be used for the purposes of hypothesis 
generation only. 
 
 Missing Data and Sensitivity Analyses 
Every attempt will be made to collect full follow-up data on all study participants; it is thus 
anticipated that missing data will be minimal (less than 4%). Participants with missing primary 
outcome data (withdrawn from the study, did not undergo surgery or did not attend a follow-
up appointment) will not be included in the primary analysis in the first instance. This presents 
a risk of bias, and sensitivity analyses will be undertaken using modern multiple imputation 
techniques to assess the possible impact of the risk.  
 

 
 
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    Planned Interim Analysis  
The first and second formal interim analyses will include efficacy data alongside other 
important aspects such as adherence and acceptability, to enable the DMC to determine which 
arms to recommend being dropped. At least two research arms will be dropped from the trial 
after each interim analysis.  
 
We have 70 sites signed up to join the trial and the surgeons have stated that they are 
currently in clinical equipoise relating to the interventions being assessed in the trial. Actual 
uptake and compliance to randomised allocation will be formally assessed at the end of the 
pilot stage, and arms where clinical equipoise has not been demonstrated, as witnessed by 
the behaviour of surgeons within the trial, will be adjusted or dropped. The unique MAMS 
design will also allow us to continue this monitoring process throughout the trial; at each pre-
specified interim analysis, arms will be chosen for dropping not only on based on their efficacy 
signal but also on other aspect including compliance, acceptability and cross-over rates. There 
is the potential for ‘gravitation towards the mean’ in any trial involving a complex intervention 
where the local investigator cannot be blinded to the measures used in an individual patient. 
We think this potential for a surgeon to change their behaviour based on their experiences 
within the trial is unlikely because the interventions under study are binary (i.e. they are either 
used or they are not), limiting the opportunities for changes in practice within the trial. 
 
    Planned Final Analyses  
The primary analysis for the study will occur once all participants have completed the 30-day 
assessment and corresponding outcome data has been entered onto the trial database and 
validated as being ready for analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 Health economic analysis 
Economic evaluation will be carried out to determine the costs and benefits of the compared 
interventions, with a view to establishing the practice that represents best use of NHS 
resources. In line with recommendations, the base case analysis will be conducted from the 
perspective of the NHS and personal social services. Additional analysis will adopt a wider, 
societal perspective. Results will be presented in terms of cost per additional quality-adjusted 
life year (QALY) gained. To avoid collecting large amounts of data from trial participants in 
those arms that would eventually become obsolete, health economic analysis will start in the 
final stage of the ROSSINI 2 to provide assessment of the most effective trial interventions.   
 
    Resource use and costs 
Information on use of health care resources will be collected alongside the proposed trial 
through CRFs and patient questionnaires. Relevant data will include: i) costs associated with 
the purchase and use of the assessed in-theatre interventions under assessment ii) costs 
associated with the use of postoperative care provided in response to surgical wound 
infections in the hospital setting (e.g. inpatient stay, outpatient appointments, additional 
procedures related to wound infection, use of antibiotics) iii) costs due to use of primary care 
services (GP consultations, appointments with nurses, antibiotics and painkillers provided in 
the community) and, iv) private (patient) costs and productivity loss related to wound healing. 
Use of health care resources will be weighted by unit cost values taken from up-to-date 
national sources and tariffs, including the Unit Cost of Health and Social Care report (70), the 
British National Formulary and the NHS Reference Cost Schedules. 
 
    Outcomes  
The main measure of benefit in the economic evaluation will be the quality-adjusted life year 
(QALY), an outcome that combines expected survival and QoL. QoL will be obtained through 
patients’ responses to the 5-level European Quality of life (EQ-5D-5L) (73) instrument at 
baseline, 7 days and 30-days post-operation. Each patient’s health status descriptions 
obtained from the EQ-5D-5L will be translated into a single, preference-based (utility) index 
using a UK specific value set (74). QALYs will be calculated as the area under the curve 
connecting utility scores reported at the above follow-up points. 
 
    Analysis  
Given the nature and time frame of the clinical question, relevant costs and outcomes are 
expected to be largely captured within the study follow-up period. Thus, the main analysis will 
be carried out on the basis of patient-level data obtained within the trial follow-up. Data will 
be analysed on an ‘intention to treat’ basis. Missing data will be accounted for by using 
appropriate techniques, depending on the extent and type of missing items (75). As the 
distribution of cost is usually skewed by the existence of patients with very high costs, the 
calculated mean per patient cost will be given alongside confidence intervals obtained through 
non-parametric bootstrap methods (76). Incremental analysis will be undertaken to calculate 
the difference in costs and the difference in outcomes (QALYs) associated with each of the 

 
 
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interventions. Results will be presented in the form of incremental cost-effectiveness ratios 
(ICER), reflecting the extra cost for an additional unit of outcome. To account for the inherent 
uncertainty due to sampling variation, the joint distribution of differences in cost and outcomes 
(QALYs) will be derived by carrying out a large number of non-parametric bootstrap 
simulations (77). The simulated cost and outcome pairs will be depicted on a cost-
effectiveness plane and will be plotted as cost-effectiveness acceptability curves (CEACs) (78). 
CEACs will show the probability of each intervention being cost-effective across a range of 
possible values of willingness to pay for an additional QALY. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 TRIAL ORGANISATIONAL STRUCTURE 
The Chief Investigator will have overall responsibility for the trial. The co-applicants will form 
the Trial Management Group (TMG) and will meet at least quarterly to discuss and coordinate 
the project. The project involves close interaction between two established CTUs. The MRC 
CTU are experts in MAMS trial design and analysis. As well as ongoing input into the design 
and conduct of the trial, they will oversee the statistical team at BCTU in undertaking the data 
analysis, thereby disseminating specialist knowledge and further enhancing long-lasting 
benefits from this collaboration going into future projects. The coordinating centre at the 
University of Birmingham will employ trial-specific staff to manage the trial for the project 
duration. The trial manager will undertake all day-to-day conduct of the trial with oversight 
provided by a trials management team leader. Given the size and complexity of the trial, a 
senior data manager and a data manager will also be appointed to assist in the management 
and data collection of the trial. In addition to the TMG meetings, the CI and the BCTU trial 
staff will meet on a monthly basis for ongoing and continual review of trial. A Trial Steering 
Committee will be formed and chaired by an independent chair and will also comprise a patient 
representative, the Chief Investigator, the trial statistician (if required), an independent 
surgeon and a clinical trialist. The Independent DMC will consist of an independent statistician 
and independent clinicians. Its meetings will mirror those of the Trial Steering Committee, and 
will usually occur 2-4 weeks prior to the Trial Steering Committee meeting. Patients will be at 
the centre of our project throughout, and their input, both via the named patient co-applicants 
will be contemporaneously inputted into the management processes as the trial progresses. 
 
    Sponsor 
The University of Birmingham is the sponsor for this trial. It takes overall responsibility for 
initiation, management and financing of the trial. 
 
    Coordinating Centre 
The ROSSINI 2 Trial Office is based at the University of Birmingham Clinical Trials Unit 
(BCTU). 
 
    Trial Management Group 
The Trial Management Group (TMG) is responsible for the day to day management of the trial. 
Membership of the TMG is listed at the front of the protocol. The role of the TMG is to monitor 
all aspects of the conduct and progress of the trial, ensure that the protocol is adhered to and 
take appropriate action to safeguard participants and the quality of the trial itself. 
 
    Trial Steering Committee  
A TSC will be created for the ROSSINI 2 Trial and meet via tele/video-conference or face-
to-face, as required depending on the needs of the trial or at the request of the DMC to 
coincide with the timing of the interim analyses. 

 
 
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Membership and duties/responsibilities are outlined in the TSC Charter. The role of the TSC is 
to provide the overall supervision of the trial, including the practical aspects of the trial. 
Membership of the TSC is listed at the front of the protocol. The TSC will monitor trial progress 
and conduct, and provide advice on scientific credibility. The TSC will consider and act, as 
appropriate, upon the recommendations of the DMC or equivalent and ultimately carries the 
responsibility for deciding whether the trial needs to be stopped on grounds of safety or 
efficacy. 
 
    Data Monitoring Committee  
Data analyses will be supplied in confidence to an independent DMC, which will be asked to 
give advice on whether the accumulated data from the trial, together with the results from 
other relevant research, justifies the continuing recruitment of further participants. 
 
The DMC will operate in accordance with a trial specific ROSSINI 2 DMC charter based upon 
the template created by the Damocles Group. The DMC will meet at the following interim 
analysis time points unless there is a specific reason (e.g. safety phase) to amend the 
schedule: 
• 
Review of the Pilot Stage - this was not a formal interim analysis and no analyses of 
efficacy occurred, however the DMC reviewed progress against the Pilot Stage 
objectives and approved the continuation of the trial into the Main Phase. 
• 
First interim analysis at 2357 patients 
• 
Second interim analysis at 4632 patients 
• 
Final analysis at approximately 6610 patients 
 
Please note: Number of patients and stages may be subject to change. 
 
Additional meetings may be called if recruitment is much faster than anticipated and the DMC 
may, at their discretion, request to meet more frequently or continue to meet following 
completion of recruitment. An emergency meeting may also be convened if a safety issue is 
identified. The DMC will report directly to the TSC who will convey the findings of the DMC to 
the TMG and/or the, REC or funders if required. The DMC may consider recommending the 
discontinuation of the trial if the recruitment rate or data quality are unacceptable or if any 
issues are identified which may compromise participant safety. The trial will stop early if the 
interim analyses showed differences between interventions that were deemed to be 
convincing to the clinical community.  
 
 
 
 
 
 
 
 
 

 
 
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 ETHICAL CONSIDERATIONS  
The trial will be conducted in accordance with the UK Policy Framework for Health and Social 
Care Research, the applicable UK Acts of Parliament and Statutory Instruments, (and relevant 
subsequent amendments) which include, but are not limited to, the Medicines for Human Use 
(Clinical Trials) Regulations 2004 and the Data Protection Act 2018.   
 
The trial will be carried out according to the Principles of GCP as set out in the UK Statutory 
Instrument (2004/1031; and subsequent amendments). 
 
The protocol will be submitted to and approved by the main REC prior to the start of the trial. 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site File, 
and an annual progress report (APR) will be submitted to the REC within 30 days of the 
anniversary date on which the favourable opinion was given by the REC, and annually until 
the trial is declared ended.  
 
Before any participants are enrolled into the trial, the PI at each site is required to obtain local 
R&D approval/assurance. Sites will not be permitted to enrol participants until written 
confirmation of R&D approval/assurance is received by the BCTU trials team. 
 
It is the responsibility of the PI to ensure that all subsequent amendments gain the necessary 
local approval. This does not affect the individual clinicians’ responsibility to take immediate 
action if thought necessary to protect the health and interest of individual participants.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 CONFIDENTIALITY AND DATA PROTECTION 
Personal data recorded on all documents will be regarded as strictly confidential and will be 
handled and stored in accordance with the Data Protection Act 2018 (and subsequent 
amendments). 
 
Participants will always be identified using only their unique trial identification number on the 
CRF and correspondence between the Trials Office and the participating site. Participants will 
give their explicit consent for the movement of their consent form, giving permission for BCTU 
to be sent a copy (upon request). This will be used to perform central monitoring of the 
consent process.  
 
The PI must maintain documents not for submission to BCTU (e.g. Participant Identification 
Logs) in strict confidence. In the case of specific issues and/or queries from the regulatory 
authorities, it will be necessary to have access to the complete trial records, provided that 
participant confidentiality is protected. 
 
BCTU will maintain the confidentiality of all participant’s data and will not disclose information 
by which participants may be identified to any third party other than those directly involved 
in the treatment of the participant and organisations for which the participant has given 
explicit consent for data transfer. Representatives of the Birmingham Clinical Trials Office and 
Sponsor may be required to have access to participant’s notes for quality assurance purposes 
but participants should be reassured that their confidentiality will be respected at all times. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 FINANCIAL AND OTHER COMPETING INTERESTS 
ROSSINI 2 is an investigator-initiated and investigator-led trial funded by the NIHR Health 
Technology Assessment Programme. All interventions, including training are provided free-of-
charge by BD Infection Prevention (Skin Prep), 3M Infection Prevention (Drapes) and SERB 
(Sponges). 
The trial design, data collection, analyses and interpretation of the findings remain under 
control of the TMG. No competing interests are declared.  
Members of the TSC and DMC are required to provide declarations on potential 
competing/conflicts of interests as part of their membership of the committees.  
 
 INSURANCE AND INDEMNITY  
The University of Birmingham has in place Clinical Trials indemnity coverage for this trial which 
provides cover to the University for harm which comes about through the University’s, or its 
staff’s, negligence in relation to the design or management of the trial and may alternatively, 
and at the University’s discretion provide cover for non-negligent harm to participants. With 
respect to the conduct of the trial at Site and other clinical care of the patient, responsibility 
for the care of the patients remains with the NHS organisation responsible for the Clinical Site 
and is therefore indemnified through the NHS Litigation Authority. The University of 
Birmingham is independent of any pharmaceutical company, and as such it is not covered by 
the Association of the British Pharmaceutical Industry (ABPI) guidelines for participant 
compensation. 
 
 SUB-STUDIES 
    Microbiology Sub-Study 
Whilst we are not using microbiological parameters to diagnose SSI alone, it is prudent to 
consider that the mechanism of action of all of the interventions under assessment could be 
influenced by the local concentrations of all, or certain subtypes of pathogenic organisms 
present within the wound. As such, there are two objectives  within this sub-study that may 
provide confirmatory evidence of our clinical efficacy findings: 
 
1. Patients diagnosed with a SSI after an operation will usually have a wound swab taken by 
their clinician as part of standard practice, either in hospital or in the community. As such, for 
patients in whom our routine follow-up tools identify a culture result, we will request that the 
site forward any available pus swab laboratory results listing the organisms and sensitivities 
identified. This will allow us to identify if certain interventions or combinations of interventions 
are more effective at reducing certain causative organisms of SSI. It may allow future tailoring 
of combinations of interventions to try to target all relevant types of pathogenic organisms 
causing SSI. 
 
2. In 20 random patients in each arm (160 patients total), intraoperative swabs will be taken 
in theatre at two time points: (1) from the skin/fat of the wound at the end of the intra-
abdominal component; (2) then from the skin surface after closure. This will allow assessment 

 
 
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of which organisms are present in the wound at the end of the operation depending on which 
intervention(s) are used. We anticipate that this sub-study will be undertaken at our index 
hospital site (University Hospitals Birmingham) only. 
 
 ACCESS TO FINAL DATA SET 
The final dataset will be available to members of the Trial Management and co-applicant group 
who need access to the data to undertake the final analyses. 
 
Requests for data generated during this study will be considered by BCTU. Data will typically 
be available six months after the primary publication unless it is not possible to share the data 
(for example: the trial results are to be used as part of a regulatory submission, the release 
of the data is subject to the approval of a third party who withholds their consent, or BCTU is 
not the controller of the data).  
 
Only scientifically sound proposals from appropriately qualified Research Groups will be 
considered for data sharing. The request will be reviewed by the BCTU Data Sharing 
Committee in discussion with the CI and, where appropriate (or in absence of the CI) any of 
the following: the Trial Sponsor, the relevant TMG, and independent TSC.  
 
A formal Data Sharing Agreement (DSA) may be required between respective organisations 
once release of the data is approved and before data can be released. Data will be fully de-
identified (anonymised) unless the DSA covers transfer of participant identifiable information. 
Any data transfer will use a secure and encrypted method. 
 
 PUBLICATIONS AND OUTPUTS  
    Authorship policy 
Results and analyses of this trial data will be submitted for publication in a peer reviewed 
journal. The manuscript will be prepared by the Chief Investigator and authorship will follow 
the National Research Collaborative model for publication (76). All investigators will be listed 
as collaborating authors under a single corporate author group; “ROSSINI 2 Trial Group; 
West Midlands Research Collaborative”. The writing group, trial management group, TSC, 
DMC, site principal investigators and associate principal investigators, and site co-investigators 
will be grouped in order to outline their specific level of contribution. Recruitment and 
randomisation of at least ten patients into the trial will qualify an investigator for co-authorship 
status. 
  
    Publications and impact 
This complex trial will provide high-level evidence on the clinical efficacy and cost-
effectiveness of several interventions used to try and reduce SSI. The multi-arm, multi-stage 
nature of the trial means that outcomes information will become available at multiple time 
points throughout the trial course. As such, planning a publication schedule is difficult and the 
TMG will likely choose to release major clinical effectively results at more than one juncture 

 
 
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in addition to at completion of the trial. The timings of these reports will be carefully 
considered to not negatively affect the trial whilst ensuring that ineffective interventions are 
dropped from the general surgical armamentarium as soon as possible to help save money 
for the NHS.  
 
We will aim for several high impact factor peer-reviewed publications from this project, 
including the Lancet, Lancet Infectious Disease, British Medical Journal and Annals of Surgery.  
In addition: 
• 
Reports and presentations will be prepared for the funders, ethics committee, local 
NHS Trusts and in addition a lay summary will be prepared for regional and national 
patient groups.  
• 
We will also work with our patient representatives to produce information leaflets for 
routine use in NHS centres.  
• 
A report will be sent to the WHO patient safety panel for their consideration in the 
derivation of future SSI prevention and reduction guidelines. 
• 
National and European guidelines: our trial management group contains members of 
several national and international groups and are thus in a position to directly influence 
future specialty guidelines on this topic. 
• 
NICE guidance: we will work with NICE to produce best guidance information for 
commissioners and clinicians. 
Any secondary publications and presentations prepared by Investigators must be reviewed 
and approved by the TMG. Manuscripts must be submitted to the TMG in a timely fashion and 
in advance of being submitted for publication, to allow time for review and resolution of any 
outstanding issues.  Authors must acknowledge that the trial was performed with the support 
of Birmingham Clinical Trials Unit with funding from a Health Technology Assessment grant 
from the National Institute of Health Research.  Intellectual property rights will be addressed 
in the Clinical Study Site Agreement between Sponsor and site. If centres in Northern Europe 
open and recruit for ROSSINI 2, individual countries will be allowed to publish their efficacy 
results, however the publication of efficacy results from the pooled analysis will take 
precedence over efficacy result publications of individual countries, unless the TMG decides 
otherwise. Participants will be provided with the trial results after the Final Trial Report had 
been compiled and/or after the paper describing the primary outcome had been published.  
 
    Presentations 
We will present at national and international meetings, including the Association of Surgeons 
of Great Britain and Ireland, the Association of Coloproctology of Great Britain and Ireland, 
the European Society of Coloproctology, the American College of Surgeons Annual Clinical 
Congress and the Society of Clinical Trials. This will capture an extremely large audience of 
clinicians nationwide and worldwide. The major UK conferences will be approached to organise 
yearly sessions to highlight progress of the trial and then a plenary session to report results.  
 
 
 
 

 
 
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 Associate Principal Investigator Scheme  
One principal investigator and at least one associate principal investigator (API) per surgical 
specialty open will be permitted at each site. The first site principal investigator to register will 
hold overall responsibility for the site trial conduct, and will be responsible for submitting a 
final authorship list from each site. Multiple APIs per site will be permitted, providing they 
complete their six-month minimum tenure and achieve formal API sign-off by the NIHR co-
ordinating centre. The API will undertake a variety of defined roles including: supporting trial 
approvals, helping with site set-up, co-ordinating within team communication, recruitment, 
co-ordination of other trial team members and support Birmingham Clinical Trials Unit (BCTU) 
to ensure that all members of the trial team have completed mandatory training, and signed 
the 
delegate 
log. 
For 
more 
information 
on 
the 
API 
scheme 
please 
see: 
https://www.nihr.ac.uk/documents/associate-principal-investigator-pi-scheme/25040  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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 Table of Appendices 
Appendix 1 
Superseded Trial Schema 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 1. Superseded Trial Schema