Clinical trial NCT02389036: Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients
Official title: A Crossover, Cluster Randomised Controlled Trial of Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Critical Illness
Sepsis
Septic Shock
Ventilator Associated Pneumonia
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: Imperial College London
name: Sunnybrook Health Sciences Centre
First posted: 2015-03-17
Enrollment: 20010
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Cluster, crossover, randomized clinical trial
Primary purpose: PREVENTION

Brief summary: Introduction- Hospital acquired infections (HAI) are a major cause of morbidity and mortality and increase health care costs. Critically ill patients are particularly susceptible to these infections and have an even higher mortality. One intervention that has gained much interest in the medical literature for reducing infection rates and deaths from HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of antibiotic paste to the mouth, throat, stomach and a short course of intravenous antibiotics. The evidence supporting the use of SDD for saving lives and preventing infections is actually quite strong. However, health care professionals in many parts of the world have refrained from using SDD due to fears of the effects of overuse of antibiotics on the frequency of infections with resistant bacteria such as multi-resistant Gram negative organisms, MRSA and Clostridium difficile.

SuDDICU is a cross-over, cluster randomised trial comparing the effect of using selective decontamination of the digestive tract (SDD) plus standard care, to standard care alone on hospital mortality in patients receiving mechanical ventilation in the intensive care unit (ICU).

Secondary outcomes include an ecological assessment and a long-term health economic analysis.

Detailed description: Design- international, multicentre, crossover, cluster randomised controlled trial (x-cRCT) of eligible patients in participating ICUs using two 12-month interventional trial periods separated by a 3-month inter-period gap.

An observational ecological assessment will be conducted in all ICU patients during one week of each month during the 3-month surveillance period before the first intervention period; in all trial eligible patients during the two 12-month intervention periods; in all ICU patients during one week of each month of the final 3-months of the two intervention periods; in all ICU patients during one week of each month during the 3-month inter-period and post-trial periods.

Participants- General ICUs that admit mechanically ventilated patients will be randomised in the first 12-month period to either implement the SDD protocol in addition to standard care or to continue standard care without SDD, and then to cross over to the other arm during the second 12-month period.

Eligible patients are defined as:

1. All patients who are mechanically ventilated via an endotracheal tube on admission to the ICU and who are predicted to remain ventilated beyond the end of the calendar day after the day of ICU admission, or
2. All patients who become mechanically ventilated via an endotracheal tube during their ICU stay and who are predicted to remain ventilated beyond the end of the calendar day after the day they are first ventilated, or
3. All patients who not already recruited but are receiving mechanical ventilation via an endotracheal tube and are expected to receive ongoing ventilation for a further 48-hours or more despite an earlier prediction that ventilation would be discontinued earlier.

All patients eligible for the intervention will receive the following in addition to the usual infection control measures:

1. 1. A six-hourly topical application of 0.5g paste, containing colistin 10mg, tobramycin 10mg and nystatin 125,000 IU, to the buccal mucosa and oropharynx
2. A six-hourly administration of 10 mL of a suspension containing 100 mg colistin, 80 mg tobramycin and 2 x 106 IU nystatin, to the gastrointestinal tract via a gastric/post-pyloric tube
3. A four-day course of an IV antibiotic. Patients not already receiving a therapeutic antibiotic will be prescribed cefotaxime 1g six-hourly or ceftriaxone 1g daily, with dose adjusted as appropriate for organ dysfunction. Ciprofloxacin (400mg 12-hourly) may be used as an alternative if there is a contraindication to cephalosporins (e.g. allergy). Patients already receiving an alternative IV antibiotic to treat infection will not receive this additional IV antibiotic, but will continue the prescribed antibiotic for the usual duration of therapy.

Statistical considerations and sample size- SuDDICU will recruit 10 000 to 15 000 patients from 29 ICUs and will have 80% power to detect an absolute reduction in hospital mortality of 3-5% from a baseline mortality of 29%, depending on the precise number of clusters.

Eligibility criteria: Inclusion Criteria:

Site inclusion for cluster study- A general ICU or complex of ICUs (medical, surgical, mixed) capable of treating mechanically ventilated critically ill adult patients.

Patient inclusion criteria

1. All patients who are mechanically ventilated via an endotracheal tube on admission to ICU and who are predicted to remain ventilated beyond the end of the calendar day after the day of ICU admission, or
2. All patients who become mechanically ventilated via an endotracheal tube during their ICU stay and who are predicted to remain ventilated beyond the end of the calendar day after the day they are first ventilated, or
3. All patients not already recruited who are receiving mechanical ventilation via an endotracheal tube and are expected to receive ongoing ventilation for a further 48 hours or more despite an earlier prediction that ventilation would be discontinued earlier.

Site exclusion criteria for cluster study-

1. Unwilling or unable to follow trial protocols.
2. Unable to capture the minimum data set required for the study.
3. Isolated specialty ICUs not co-located with a general ICU, such as solely cardiac, neurological/neurosurgical and burns ICUs, but such specialty patients cared for in general ICUs will be included
4. Specialty paediatric ICUs

Exclusion Criteria:

Patient exclusion criteria

1. Patients enrolled in a trial that would interact with the intervention
2. Patients with a known allergy, sensitivity or interaction to trial topical intervention drugs
3. Patients who are known or suspected to be pregnant
4. Patients who are moribund and not expected to survive the next 12 hours
5. Patients less than 16 years of age will not be enrolled in the UK

Primary outcomes:
measure: Hospital Mortality
timeFrame: Hospital discharge [up to Day 90 after randomization]
Secondary outcomes:
measure: Total antibiotic usage
timeFrame: during ICU admission
measure: The incidence of antibiotic resistant organisms in cultures from blood or other sterile sites
timeFrame: during ICU admission
measure: The incidence of antibiotic-resistant organism in non-sterile clinical and surveillance specimens
timeFrame: during ICU admission
measure: The incidence of C. difficile infections
timeFrame: during ICU admission
measure: Changes in antibiotic resistance rates between study epochs (pre-trial, interperiod gap and post-trial) within groups
timeFrame: Through out all study periods
measure: Duration of mechanical ventilation
timeFrame: Time of enrolment to ICU discharge within index hospital admission,[up to Day 90 after randomization]
measure: ICU length of stay
timeFrame: From the time of enrolment to ICU discharge, [up to Day 90 after randomization]
measure: Hospital length of stay
timeFrame: From time of enrolment to hospital discharge within the index hospital admission, [up to Day 90 after randomization]
measure: ICU Mortality
timeFrame: ICU discharge [up to Day 90 after randomization]
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: The George Institute for Global Health
state: New South Wales
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: The George Institute
name: John Myburgh, MBBCh PhD
role: STUDY_CHAIR
affiliation: Sunnybrook Health Sciences Centre
name: Brian Cuthbertson, MD FRCA
role: STUDY_CHAIR
affiliation: Imperial College London
name: Anthony Gordon, MD FRCA
role: STUDY_CHAIR
References:
citation: Cuthbertson BH, Campbell MK, MacLennan G, Duncan EM, Marshall AP, Wells EC, Prior ME, Todd L, Rose L, Seppelt IM, Bellingan G, Francis JJ. Clinical stakeholders' opinions on the use of selective decontamination of the digestive tract in critically ill patients in intensive care units: an international Delphi study. Crit Care. 2013 Nov 8;17(6):R266. doi: 10.1186/cc13096.
citation: Daneman N, Sarwar S, Fowler RA, Cuthbertson BH; SuDDICU Canadian Study Group. Effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis. Lancet Infect Dis. 2013 Apr;13(4):328-41. doi: 10.1016/S1473-3099(12)70322-5. Epub 2013 Jan 25.
citation: Cuthbertson BH, Francis J, Campbell MK, MacIntyre L, Seppelt I, Grimshaw J; SuDDICU study groups. A study of the perceived risks, benefits and barriers to the use of SDD in adult critical care units (the SuDDICU study). Trials. 2010 Dec 3;11:117. doi: 10.1186/1745-6215-11-117.
citation: SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group; Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M, Davis JS, Gordon AC, Hammond NE, Iredell J, Li Q, Micallef S, Miller J, Mysore J, Taylor C, Young PJ, Cuthbertson BH, Finfer SR. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2022 Nov 15;328(19):1911-1921. doi: 10.1001/jama.2022.17927.