DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



The SuDDICU Study of Antibiotic Prophylaxis in Critical Illness

Information source: The George Institute
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Critical Illness; Sepsis; Septic Shock; Ventilator Associated Pneumonia

Intervention: SDD Paste (Drug); SDD Suspension (Drug); Intravenous Antibiotic (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: The George Institute

Official(s) and/or principal investigator(s):
Brian Cuthbertson, MD FRCA, Study Chair, Affiliation: Sunnybrook Health Sciences Centre, Toronto

Overall contact:
Brian Cuthbertson, MD FRCA, Phone: 4167926860, Ext: 83735, Email: brian.cuthbertson@sunnybrook.ca

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. Aim- The investigators aim to test whether SDD is clinically effective and cost-effective at reducing mortality in mechanically ventilated critically ill patients in the intensive care without increasing antibiotic resistance. Plan of study and methods- The investigators propose a multi-national, cluster randomised, trial of SDD in critically ill patients who require mechanical ventilation in an ICU. The study includes an embedded contemporaneous study that will evaluate the ecological impact of such an intervention, as well as a detailed cost-effectiveness analysis. The investigators believe that to be definitive the SuDDICU study has to achieve two separate and equally important outcomes: 1. Demonstrate unequivocal results with regard to the effectiveness of SDD; and, equally importantly 2. Present unequivocal results with regard to the effects of SDD on antibiotic resistance patterns. For this reason, the investigators do not believe these studies can be separated. The study will be conducted in the UK, Canada, Australia and New Zealand, offering broad generalizability across a range of health care systems including systems with higher HAI rates and therefore definitively identify the role (if any) of SDD in clinical practice.

Clinical Details

Official title: The SuDDICU Study- A Randomised Trial of the Effectiveness and Cost-effectiveness With a Contemporaneous Study of the Ecological Impact of Selective Decontamination of the Digestive Tract in Critically Ill Patients Treated in ICUs.

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Hospital Mortality

Secondary outcome:

The incidence of antibiotic resistant organisms

The cost-effectiveness of the systematic delivery of SDD

Long term mortality

Quality of life Assessment

Total antibiotic usage

The incidence of antibiotic resistant organisms in cultures from blood or other sterile sites

The incidence of antibiotic-resistant organism in non-sterile clinical and surveillance specimens

The incidence of C. difficile infections

Changes in antibiotic resistance rates between study epochs (pre-trial, trial and post-trial) within groups

Detailed description: The proposed program of research design i. A multi-centre, multi-national, cluster randomised controlled trial of SDD in critically ill patients who require mechanical ventilation in the ICU (SuDDICU-RCT) ii. An embedded, contemporaneous observational ecology study assessing the incidence of antibiotic resistant organisms (AROs) in ICUs (e-SuDDICU). iii. A prospective cost-effectiveness evaluation of SDD use from the health system perspective over a lifetime horizon (SuDDICU-CEA) Aim- We aim to test whether SDD is clinically effective and cost-effective at reducing mortality in mechanically ventilated critically ill patients in the ICU without increasing antibiotic resistance Primary hypotheses- The systematic delivery of SDD to critically ill patients within an ICU will: 1. Reduce hospital mortality and 2. Not increase the incidence of antibiotic resistant organisms isolated from clinical and surveillance specimens in those ICUs and 3. Be cost-effective in comparison to the current standard of care not including SDD Secondary hypotheses- 1. Does the systematic delivery of SDD to critically ill patients within an ICU increase the incidence of antibiotic resistant organisms isolated from clinical and surveillance specimens in those ICUs? 2. Is the systematic delivery of SDD to critically ill patients within an ICU cost-effective in comparison to the current standard of care not including SDD? Secondary infection hypotheses- The systematic delivery of SDD to critically ill patients within an ICU will: 1. Reduce total antibiotic use in those units randomised to SDD 2. Not increase the incidence of antibiotic resistant organisms in cultures from blood or other sterile sites in those units 3. Not increase the incidence of antibiotic-resistant organism in non-sterile clinical and surveillance specimens in those units 4. Not increase the incidence of C. difficile infections during ICU admission in those units Primary research question- Does the systematic delivery of SDD to critically ill patients within an ICU reduce hospital mortality? Duration of treatment period- Mechanically ventilated patients will be treated with SDD from immediately after ICU admission (within 6 hours), or within 6 hours from the time of intubation if this occurs after ICU admission. The topical and enteral intervention will continue until extubation or removal of the enteral feeding tube or 24 hours spontaneous ventilation via tracheostomy without support, or ICU discharge. The intravenous antibiotic will be continued for 4 days or until ICU discharge, whichever comes first. Blinding of the intervention- We will not blind the intervention. Standard of care interventions in both trial arms- We recommend control and SDD group management is in line with current national standards of practice that may or may not include a VAP bundle. Compliance with intervention and the process evaluation- We predict that once centres are randomised, their patients will receive the intervention in the vast majority of cases (>90%). To assure compliance we will closely monitor the intervention to ensure high compliance. Separate to the trial compliance monitoring we will conduct a trial process evaluation. Health economic issues There will be separate cost-effectiveness (CEA) and cost-utility (CUA) analyses undertaken in each country. Data collection for the CEA and CUA will be performed in a random sample of patients in each site in line with the power calculation below. The embedded, contemporaneous, ecology study assessing the incidence of antibiotic resistant organisms (AROs) in ICUs (e-SuDDICU)- Study periods and outcomes- We acknowledge that changes in infection and the incidence of antibiotic resistance over time are key issues. To identify baseline rates in all units and across all study countries, e-SuDDICU will start data collection 6 months before the intervention (pre-trial period). During this period all standard practices will continue in line with local protocol and ICUs will be randomised to either the control or intervention groups with stratified group allocation. For SDD units, pre-trial education and intervention implementation will occur at this stage (see below). To monitor the effects of SDD on the incidence of antibiotic resistance, e-SuDDICU will continue data collection throughout the 12-month trial period and a further 12-month post-trial period. Definitions- Choosing appropriate and valid definitions for e-SuDDICU is key as we are using a primary outcome examining the incidence of antibiotic resistance. This requires a unified outcome definition. For the ecology study we have chosen the following definitions for key data points and outcomes. Antibiotic Resistant Organism- Are defined using the Dutch Nosocomial Infection Guidelines. Total antibiotic use- Defined daily doses of all antibiotics by all routes. Sterile site

cultures - are defined as blood, pleural fluid, peritoneal fluid, cerebrospinal fluid,

sterile aspirate or tissue biopsy. Clinical or surveillance specimens- Are defined as either routine clinical microbiology specimens and protocolised admission standardized microbiology surveillance specimens or routine clinical surveillance specimens in all ICU admissions during the index ICU admission. SuDDICU sample size and plan of analysis Proposed sample size Anticipating similar proportions of enrolment among participating country ICUs, we have identified an expected overall average hospital mortality (CER) for our targeted patients of 29% Effect size- We intend to power the study to look for an absolute risk reduction for hospital mortality of 3. 5%, from 29% to 25. 5%. This reduction is based on what we believe to be an appropriate minimally clinically important difference for a mortality benefit in critical care patients and in previous well designed studies with values in high quality large positive studies Power and intercluster correlation coefficient (ICC)- We powered the study with an alpha of 5% and a beta of 90% power. With regard to ICC, we have identified an ICC of 0. 01 RCT sample size- A total of 22,500 patients or 11,250 per group. Allowing for loss to follow-up, which due to the nature of the effectiveness primary outcome (hospital mortality) we predict to run at approximately 1% and a further 4% of failure to consent rate, we plan to recruit 23,600 patients or 11,800 per group. Our power calculation also dictates we need 100 clusters. Planned recruitment rate and period- With 100 clusters recruiting 30,569 patients per year we would expect to recruit the target patient number (23,500) in 10 months of clinical recruitment. We have conservatively inflated this number taking the recruitment period to 12 months. Plan of analyses SuDDICU-RCT- The proposed SuDDICU-RCT is a cluster RCT, where ICUs will be the unit of randomisation, but outcome data will be collected at the level of the individual participant. The primary outcome, hospital mortality, will be analysed within a multi-level modeling framework. As the primary outcome is binary we will use logistic regression models with a random effect for ICU. We plan both a simple unadjusted analyses and an adjusted analysis that will include prognostic covariates. The unadjusted analyses will include only treatment allocation and ICU. The adjusted analyses will include prognostic covariates at the level of the participant (e. g. nature of ICU admission (surgery, trauma etc.) and ICU level covariates (e. g. ICU baseline antibiotic resistant rates etc). We plan to explore potential treatment modification within these subgroups by including treatment by subgroup interactions in models. We also plan to explore the effects of potential post-admission treatment mediators. All participants will be analysed according to the intention-to-treat principle. Potential mediators of treatment effects will be explored within a casual methods framework, including if treatment received was as allocated. We will also perform a variety of sensitivity analyses around the primary outcome including hospital mortality in patients actually recruited to the SuDDICU-RCT; mortality outcomes at intensive care discharge, 3 and 6 months. We believe that our data collection methods including a reliance on existing clinical data sources will minimise missing outcome data and our primary analysis strategy will be on complete cases. However, we acknowledge that for a small number of cases we may not know the mortality status of participants. We will describe any missing data in detail, and if required, will test the robustness of our primary analysis using appropriate missing data strategies. e-SuDDICU- The primary analysis for e-SuDDICU will be to examine the incidence in ARO rates in the SDD and control groups within the trial period. Secondarily, antibiotic resistance rates will be monitored across the pre-trial, trial and post-trial periods within each group using interrupted time series methods, thereby controlling for heterogeneity in microbiology practices. Furthermore, as part of our specified outcomes analyses, we will have the opportunity to evaluate resistance with both clinical and surveillance samples, and will be able to determine whether rates are different among control and SDD ICUs for each method of resistance detection. Outcomes that are composite outcomes (such as incidence of ARO) will have components analysed individually to determine the direction of individual outcome effects. Sensitivity analysis will be conducted around the primary and some secondary outcomes. This will include analysing the unit-based outcomes normalised to "per 1000 patient days" rather than "per 1000 patient admissions". The reason for this analysis is that this metric will make more allowance for longer stay patients with multiple infections and allow us to determine whether any movement in the main outcomes are being driven by affects in this patient group. In a separately funded sub-study and commencing immediately after the planned one year follow up period, a study with 5-year follow-up will take place in selected ICUs to examine longer-term impact of this intervention on primary and secondary outcomes. Weighing up the effectiveness and ecology primary outcomes is a challenge in such a study when one outcome is patient based (hospital mortality) and the other is unit based (antibiotic resistance). We are currently developing a decision analysis framework to aid with the interpretation of these primary outcomes. Planned subgroup analyses Baseline (moderator) variables 1. Nature of admission (i. e. surgical (elective and emergency), trauma and medical patients) 2. Unit's baseline antibiotic resistance rates derived from pre-trial period 3. Number of admissions per year stratified by quartile of participating units 4. Unit ventilator occupancy as a percentage Post-admission (mediator) variables 1. Baseline severity of illness as determined by ICU admission APACHE II score 2. Oral chlorhexidine prophylaxis 3. Patients ICU admission baseline surveillance swab showing antibiotic resistant organism The proposed frequency of analyses- There will be one final analysis of the data. Proposed frequency and duration of follow up- All patients will be followed up at ICU and hospital discharge. A randomly selected cohort of patients from all centres will be followed up at 90 days and six months for mortality, quality of life and health economic data collection. Loss to follow-up- We predict a very small loss to follow up (1%) as the primary outcome is hospital mortality.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 invasively mechanically ventilated on admission to ICU and are predicted to remain ventilated beyond the end of the calendar day after the day of ICU admission. 2. All patients who become invasively mechanically ventilated during their ICU stay and are predicted to remain ventilated beyond the end of the calendar day after the day they are first ventilated. 3. All patients not already recruited who are receiving invasive mechanical ventilation and now are expected to receive ventilation for 48 hours 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 (non 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 (but general ICUs that also manage critically ill children will be included and children will be enrolled into the study). Exclusion Criteria: Patient exclusion criteria 1. Enrolled in a trial that would interact with the intervention (e. g. an trial of a medicinal product with specific antibiotic (not antiseptic) activity). 2. Known allergy, sensitivity or interaction to trial topical intervention drugs. Note:- an allergy to the IV component of the intervention would not lead to trial exclusion but to a change in the IV component (as defined in section 4. 2.1). 3. Known to be pregnant . 4. Moribund and not expected to survive the next 12 hours (patients are eligible despite an active treatment limitation order (any form of limitation of therapy order) if mechanical ventilation is anticipated for 48 hours or more, according to inclusion

criteria i - iii above).

Locations and Contacts

Brian Cuthbertson, MD FRCA, Phone: 4167926860, Ext: 83735, Email: brian.cuthbertson@sunnybrook.ca

Additional Information

Starting date: April 2016
Last updated: March 9, 2015

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017