ROSSINI 2 - Reduction of Surgical Site Infection Using Several Novel Interventions

Sponsor

University of Birmingham (Other)

Overall Status

Recruiting

CT.gov ID

NCT03838575

Collaborator

National Institute for Health Research, United Kingdom (Other), University College, London (Other)

6,610

Enrollment

Locations

Arms

35.1

Anticipated Duration (Months)

3305

Patients Per Site

94.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is 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 three in-theatre interventions to reduce SSI rates in patients undergoing surgery with an abdominal incision. ROSSINI 2 is a non-factorial superiority design with allocation of various combinations of the three interventions to be used during the same operation, via seven possible treatment arms plus one control arm initially.

Condition or Disease	Intervention/Treatment	Phase
Surgical Site Infection Surgical Wound Infection Surgery--Complications Surgery	Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP) Device: Iodophor Antimicrobial Incise Drapes (DRAPE) Device: Gentamicin-impregnated implants/ sponges (SPONGE) Other: NONE (Control)	Phase 3

Detailed Description

The primary objective of ROSSINI 2 is to determine whether three specific in-theatre interventions, alone or in combination, result in decreased rates of surgical site infection (SSI) up to 30 days post operation in adult patients undergoing abdominal surgery.

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

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

Three health technologies will be assessed versus their control arms (standard care):

2% alcoholic chlorhexidine skin preparation, versus any other standard skin preparation
Iodophor-impregnated incise drape, versus no drape
Gentamicin-impregnated implants/ sponge at closure, versus no implant

Study Design

Study Type:

Interventional

Anticipated Enrollment :

6610 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This major, multicentre, multi-arm, multi-stage (MAMS) trial with the opportunity to cease (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 endpoint of SSI, it will also pave the way for future efficient and rapid trials in other aspects of surgical care.This major, multicentre, multi-arm, multi-stage (MAMS) trial with the opportunity to cease (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 endpoint of SSI, it will also pave the way for future efficient and rapid trials in other aspects of surgical care.

Masking:

Double (Participant, Outcomes Assessor)

Masking Description:

ROSSINI 2 is a double blind 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. 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 notes or in the patient's notes. The skin around the closed wound will be wiped clean using a wet sterile towel at the end of the procedure to prevent unblinding. Clinical follow-up will be conducted by a trained surgeon or a trained member of the local research team who did not participate in the index procedure or surgery.

Primary Purpose:

Prevention

Official Title:

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 Three In-theatre Interventions, Alone or in Combination, to Reduce SSI Rates in Patients Undergoing Abdominal Surgery.

Actual Study Start Date :

Mar 1, 2019

Anticipated Primary Completion Date :

Nov 1, 2021

Anticipated Study Completion Date :

Feb 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A - NONE (Control) Any skin preparation of the surgeon's choice may be used in the control arm apart from 2.0% Alcoholic Chlorhexidine Skin Prep. No drapes or sponges of any kind may be used.	Other: NONE (Control) Any skin preparation of the surgeon's choice may be used in the control arm apart from 2.0% Alcoholic Chlorhexidine Skin Prep. No drapes or sponges of any kind may be used.
Active Comparator: B - SKIN PREP Mechanism: A broad-spectrum antiseptic to clean and prepare the skin prior to surgery. Supplier: BD	Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP) 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). Other Names: Chloraprep
Active Comparator: C - DRAPE Mechanism: A thin impregnated plastic sheet applied to the prepared skin prior to incision to maintain sterility. Supplier: 3M Infection Prevention	Device: Iodophor Antimicrobial Incise Drapes (DRAPE) 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. Other Names: Ioban Incise Drape
Active Comparator: D - 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	Device: Gentamicin-impregnated implants/ sponges (SPONGE) This intervention describes the implantation of Gentamicin-impregnated collagen implants at the time of fascial closure. Each sponge (10 by 10 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. Other Names: Collatamp G
Active Comparator: E - SKIN PREP and DRAPE See descriptions in single arms (B & C)	Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP) 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). Other Names: Chloraprep Device: Iodophor Antimicrobial Incise Drapes (DRAPE) 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. Other Names: Ioban Incise Drape
Active Comparator: F - SKIN PREP and SPONGE See descriptions in single arms (B & D)	Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP) 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). Other Names: Chloraprep Device: Gentamicin-impregnated implants/ sponges (SPONGE) This intervention describes the implantation of Gentamicin-impregnated collagen implants at the time of fascial closure. Each sponge (10 by 10 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. Other Names: Collatamp G
Active Comparator: G - DRAPE and SPONGE See descriptions in single arms (C & D)	Device: Iodophor Antimicrobial Incise Drapes (DRAPE) 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. Other Names: Ioban Incise Drape Device: Gentamicin-impregnated implants/ sponges (SPONGE) This intervention describes the implantation of Gentamicin-impregnated collagen implants at the time of fascial closure. Each sponge (10 by 10 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. Other Names: Collatamp G
Active Comparator: H - SKIN PREP and DRAPE and SPONGE See descriptions in single arms (B, C & D)	Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP) 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). Other Names: Chloraprep Device: Iodophor Antimicrobial Incise Drapes (DRAPE) 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. Other Names: Ioban Incise Drape Device: Gentamicin-impregnated implants/ sponges (SPONGE) This intervention describes the implantation of Gentamicin-impregnated collagen implants at the time of fascial closure. Each sponge (10 by 10 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. Other Names: Collatamp G

Outcome Measures

Primary Outcome Measures

SSI rate up to 30 days after surgery as defined according to the 2017 Centers for Disease Control (CDC) and Prevention Criteria. [30 days post surgery]
The CDC definition will be used in ROSSINI 2 to identify deep incisional or superficial incisional SSIs.

Secondary Outcome Measures

30-day postoperative mortality rate (POMR). [Within 30 days post surgery]
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.
30-day postoperative wound complication rate. [Within 30 days post surgery]
The 30-day postoperative 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 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.
Serious Adverse Events up to 30 days (wounds or intervention-related only). [Within 30 days post surgery]
A Serious Adverse Event (SAE) is 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 or birth defect Is otherwise considered medically significant by the Investigator As ROSSINI 2 is a non - CTIMP, BCTU will not be collecting Suspected Unexpected Serious Adverse Reactions (SUSARs). We will however be collecting Related and Unexpected SAEs. A Related and Unexpected Serious Adverse Event (RUSAE) means a SAE occurring to a research participant which in the opinion of the Chief Investigator was: 'Related' that is, it resulted from the administration of any of the research procedures, and 'Unexpected' that is, the type of event is not listed in the protocol as an expected occurrence.
Length of hospital stay after surgery as measured from the date of surgery to the date of discharge. [Measured from the date of surgery (Day 0) to the date of discharge (expected to be within 30 days.)]
Length of hospital stay after surgery will be a 'Time to event' outcome, this 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.
Hospital re-admission for wound related complications within 30 days. [Within 30 days post surgery]
Hospital re-admissions for wound related complications within 30 days after surgery will be a 'Time to event' outcome, this 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.
Occurrence of unplanned wound reopening and/or re-operations within 30 days post-operation. [Within 30 days post surgery]
Occurrence of unplanned wound reopening and/or re-operations within 30 days after surgery will be a 'Time to event' outcome, this 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.
Health-related, preference-based quality of life [Baseline, Day 7, Day 30 and if applicable Ongoing SSI (Day 60, 90, 120 etc)]
QoL will be assessed using the widely validated EuroQol EQ-5D-5L questionnaire at baseline (preoperative), as an inpatient (day 7 or at discharge if sooner) and day 30 mirroring the timings of blinded wound assessment.
Cost-effectiveness [To complete at Day 30 and if applicable Ongoing SSI (Day 60, 90, 120 etc)]
Cost effectiveness will be assessed using the Resource Usage Form to collect patient-level health resource usage both in primary and secondary care; reported in QALYs.

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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