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

Study Overview
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Brief Summary
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ROSSINI 2 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 several in-theatre interventions, used alone or in combination, to reduce SSI rates in patients undergoing surgery.

Detailed Description
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The primary objective of ROSSINI 2 is 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. At least 60 NHS hospitals in the UK will participate in ROSSINI 2. 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. Initially, the three health technologies that were assessed versus the control arm (standard care) were: 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 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.

Official Title
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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.

Conditions
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Surgical Site Infection, Surgical Wound Infection, Surgery--Complications, Surgery

Intervention / Treatment
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* Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP)
* Device: Iodophor Antimicrobial Incise Drapes (DRAPE)
* Device: Gentamicin-impregnated implants/ sponges (SPONGE)
* Other: NONE (Control)


Participation Criteria
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Eligibility Criteria
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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 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 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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. 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. This means that only 3 interventional arms (4 including the control arm) remain in the trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A - NONE (Control)<br>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)<br>* 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.<br>|
| Active Comparator: B - SKIN PREP<br>Mechanism: A broad-spectrum antiseptic to clean and prepare the skin prior to surgery. Supplier: BD | Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP)<br>* 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).<br>* Other names: Chloraprep;|
| Other: C - DRAPE<br>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 | Device: Iodophor Antimicrobial Incise Drapes (DRAPE)<br>* 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. 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.<br>* Other names: Ioban Incise Drape;|
| Active Comparator: D - SPONGE<br>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)<br>* 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.<br>* Other names: Collatamp G;|
| Other: E - SKIN PREP and DRAPE<br>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. See descriptions in single arms (B & C) | Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP)<br>* 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).<br>* Other names: Chloraprep;Device: Iodophor Antimicrobial Incise Drapes (DRAPE)<br>* 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. 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.<br>* Other names: Ioban Incise Drape;|
| Active Comparator: F - SKIN PREP and SPONGE<br>See descriptions in single arms (B & D) | Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP)<br>* 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).<br>* Other names: Chloraprep;Device: Gentamicin-impregnated implants/ sponges (SPONGE)<br>* 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.<br>* Other names: Collatamp G;|
| Other: G - DRAPE and SPONGE<br>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. See descriptions in single arms (C & D) | Device: Iodophor Antimicrobial Incise Drapes (DRAPE)<br>* 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. 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.<br>* Other names: Ioban Incise Drape;Device: Gentamicin-impregnated implants/ sponges (SPONGE)<br>* 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.<br>* Other names: Collatamp G;|
| Other: H - SKIN PREP and DRAPE and SPONGE<br>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. See descriptions in single arms (B, C & D) | Drug: 2% alcoholic chlorhexidine skin prep (SKIN PREP)<br>* 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).<br>* Other names: Chloraprep;Device: Iodophor Antimicrobial Incise Drapes (DRAPE)<br>* 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. 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.<br>* Other names: Ioban Incise Drape;Device: Gentamicin-impregnated implants/ sponges (SPONGE)<br>* 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.<br>* Other names: Collatamp G;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-day postoperative mortality rate (POMR). | 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. | Within 30 days post surgery | 
| 30-day postoperative wound complication rate. | 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. | Within 30 days post surgery | 
| Serious Adverse Events up to 30 days (wounds or intervention-related only). | 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 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. | Within 30 days post surgery | 
| Length of hospital stay after surgery as measured from the date of surgery to the date of discharge. | 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. | Measured from the date of surgery (Day 0) to the date of discharge (expected to be within 30 days.) | 
| Hospital re-admission for wound related complications within 30 days. | 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. | Within 30 days post surgery | 
| Occurrence of unplanned wound reopening and/or re-operations within 30 days post-operation. | 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. | Within 30 days post surgery | 
| 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 (day 7 or at discharge if sooner) and day 30 mirroring the timings of blinded wound assessment. | Baseline, Day 7, Day 30 and if applicable Ongoing SSI (Day 60, 90, 120 etc) | 
| Cost-effectiveness | 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. | To complete at Day 30 and if applicable Ongoing SSI (Day 60, 90, 120 etc) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multicentre, SSI, Surgical Site Infection, Infection Prevention, MAMS, Multi-arm, Multi-stage, Pragmatic, Abdominal Surgery, RCT, Pilot, Chlorhexidine, Skin Prep, Iodophor, Drape, Gentamicin, Sponge, Surgery