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Ecological Effects of Decolonisation Strategies in Intensive Care

Information source: UMC Utrecht
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: ICU-ecology (Multidrug Resistant Bacteria); ICU-acquired Bacteraemia

Intervention: Chlorhexidine oral care (CHX-Oro) (Drug); Selective oropharyngeal decontamination (SOD) (Drug); Selective Digestive Decontamination (SDD) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: MJM Bonten

Official(s) and/or principal investigator(s):
Marc JM Bonten, Prof., Principal Investigator, Affiliation: UMC Utrecht
Christian Brun-Buisson, Prof., Principal Investigator, Affiliation: UPEC Paris

Overall contact:
Nienke L Plantinga, Drs., Phone: 0031 88 75 55102, Email: N.L.Plantinga@umcutrecht.nl

Summary

Previous research has shown that applying certain treatments can reduce both the number of infections and the presence of resistant bacteria in the intensive care (ICU) and its patients. These treatments have been used as standard care throughout the world for many years, but they have not been compared to each other yet. The investigators aim to evaluate the effect of 3 different treatments on the occurrence of resistant bacteria and bacterial infections in the ICU and to establish which treatment is the best. All adult patients undergoing mechanical ventilation are eligible for this study and will receive treatment according to the study scheme. Twice weekly, sputum and rectal samples will be obtained to measure the effects. All ICU-patients will receive standard treatment, consisting of daily body washing with an antiseptic (chlorhexidine 2%), oral care and a hand-hygiene program for health care workers as endorsed by the WHO. According to 4 different study periods, each participant will receive one of the following extra treatments depending on his or her admission date:

- Standard treatment only (this is the control group)

- Chlorhexidine 1% oral gel, this is an antiseptic.

- Antibiotic mouth paste containing 3 different antibiotics (selective oropharyngeal

decontamination, SOD).

- Antibiotic mouth paste and suspension for the stomach and intestines containing 3

different antibiotics (selective digestive decontamination, SDD). All treatments will be given 4 times daily with the purpose of killing harmful bacteria in the mouth (CHX, SOD,SDD) and digestive tract (SDD). During the study the investigators will examine the effect of these treatments on:

- the occurrence of blood stream infections with certain bacteria

- cross-transmission of certain bacteria between patients

- presence of these bacteria in the respiratory tract of the patients

- patient survival

Benefits: Previous research has shown that these interventions can reduce infections in intensive care patients. Risks: The interventions performed (both cultures and treatment) are considered safe and are already given as standard care in many ICUs throughout the world. There is a slight risk that bacteria become resistant to antibiotics: this will be monitored closely during the trial.

Clinical Details

Official title: RGNOSIS: Ecological Effects of Decolonisation Strategies in Intensive Care

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome: ICU-Ecology

Secondary outcome:

Cross-transmission rates

Respiratory tract colonization

ward-level systemic antibiotic use

colonization in relation to bacteraemia

transmission capacities of different bacteria

Patient survival

bacteraemia with resistant bacteria

Detailed description: Introduction The "R-GNOSIS: Ecological Effects of Decolonization Strategies in Intensive Care" study assesses three decolonization interventions against standard care to evaluate unit wide ecological effects and compare effectiveness. Previous studies have demonstrated that decontamination interventions were beneficial to individual patients but also influence ICU ecology, affecting patients who do not receive the intervention. Decolonization with antibiotics have been shown to reduce the prevalence of resistant bacteria during treatment [de Smet et al. NEJM 2009]. Reducing the presence of these bacteria in some patients (that are decolonized), reduces cross transmission and is therefore beneficial to all patients in the unit. The decolonization strategies therefore represent an intensive care unit population rather than an individual patient intervention. In this respect the study represents a cluster-cluster randomized clinical trial which requires the intervention is undertaken on the whole ICU population [Edwards et al. BMJ 1999]. As decolonization strategies represent an ecological intervention on the whole critical care population, all patients meeting inclusion/exclusion criteria will be entered into the study according to ethics approval in each participating country. Each participating ICU will use three decolonization strategies in a randomised order. The interventions are administered four times daily to ventilated patients until extubation. The interventions will be compared to a 6 month baseline period consisting of standard care only. Standard operating procedures Standard care The baseline period is the first 6-month period and will be used to implement universal "standard care":

- Chlorhexidine 2% body washings (CHX-BW) for all ICU patients. CHX-BW ensures state of

the art standard of care to prevent carriage and transmission of (resistant) gram positive bacteria commonly residing on body surface, such as Staphylococcus aureus and Enterococci.

- A hand hygiene improvement program (HHIP) based on the program designed by the World

Health organisation (WHO). Implementation of the hand hygiene program derived from the WHO hand hygiene program ensures state of the art standard of care for transmission prevention of all relevant pathogens.

- Standard oropharyngeal care consists of oral washing with sterile water (3-4 times

daily) and tooth brush twice daily. "Standard care" will be the only protocolised intervention in the baseline period and will be used throughout the entire study. Intervention periods After the baseline period, the first decolonization regimen will be implemented. The order of regimens per ICU is decided by randomization. The three regimens are:

- Chlorhexidine oral care (CHX-Oro) with chlorhexidine 1% oromucosal gel.

- Selective oropharyngeal decontamination (SOD) with antibiotics. SOD consists of

application of a paste containing colistin, tobramycin in a 2% concentration and nystatin 1 x 10^5 units.

- Selective digestive decontamination (SDD), in which a 10 ml suspension via the

nasogastric tube containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i. u. will be added to application of SOD paste. All intervention periods last 6 months and all regimens are applied four times daily. In contrast to some other SDD studies, systemic prophylaxis with Cefotaxime (or other broad spectrum cephalosporins) will not be implemented as part of SDD. Patient recruitment All patients in the ICU receive standard care and minor anonymized personal data are collected from them. Once monthly point prevalence cultures are collected from patients in the ICU on that day.

Eligible patients in the ICU - in addition to the above mentioned - will receive one of the

interventions and will undergo surveillance sampling. More anonymized personal data are collected (including some clinical culture results). A waiver of informed consent is in place, but patients can opt out for data collection. Culture sampling Point prevalence cultures are taken once monthly from each patient present in the ICU at that moment. These include a rectal swab and a respiratory sample and serve the purpose of monitoring and evaluating ecological changes during all regimens. Surveillance cultures are taken twice weekly from included patients and also include a rectal swab and a respiratory sample. The samples are collected to measure the treatment effect. Finally, results from regularly obtained cultures for clinical purposes (blood and respiratory samples) will be recorded to measure the treatment effect. Data-collection Data-collection can be performed by two methods. All data will be "anonymised" by recoding the patient identifier (ID) to a study patient ID and by removing their personal identifiers. 1. A web based electronic case report form (ECRF) has been designed within "Research Online". This system meets all requirements according to International Conference on Harmonisation Good Clinical Practice (ICH-GCP)standards for electronic data entry with respect to safeguarding data integrity and data security regulations. 2. Automatic extraction of data from electronic patient data dossiers may be performed if technically possible without harming the patients' privacy. Data dictionary

- Data from all patients admitted to the ICU include sex, age, disease severity score,

admission/discharge date, mechanical ventilation (yes/no) and duration, ICU-survival.

- Data from included patients additionally include: hospital admission date, place before

admission, reason for ICU admission, acute illness (yes/no), sites of organ failure, antibiotic use on ICU-admission (yes/no), comorbidity, ventilation data, disposition at 28-days after ICU- admission, at ICU-discharge and at hospital-discharge, isolation precautions.

- Culture data include results from clinical respiratory and blood samples and

surveillance cultures from included patients and point prevalence cultures (monthly) from all patients.

- Ward-level antibiotic use will be recorded per study period.

Sample size calculation In a Dutch SDD ICU trial the day-28 mortality rate during the baseline period was 27. 5% (3). Assuming a low level of cluster-effects, 2016 patients are needed in each phase to demonstrate a 10% relative reduction in day-28 mortality as compared to Standard Care (alpha=0. 05; beta=0. 8). We intend to include 2700 patients per arm. The margin of 600 patients per arm is included to allow for adjustment for differences in baseline characteristics in a random-effects logistic regression model if needed, or to include cluster-effects. Of note, assuming day-28 mortality in standard care to be 27%, the absolute reduction that can be demonstrated is 2. 7%. Day-28 mortality data will be derived from clinical data obtained as part of routine standard care. Statistical analysis plan Analysis will determine the effect of each intervention on colonization rates, the occurrence of bacteremia and the use of antibiotics. Statistical analysis of the primary objective and secondary objectives regarding mortality, antibiotic use and rate of colonisation and bacteraemia will include the use of random-effect logistic regression models to account for ICU-level clustering. Measured confounding factors will be fitted as covariates. Outcome will be presented as odds ratios. All available data on patient colonization with MDR-GNB (both from screening and clinical cultures) will be used to determine, as carefully as possible, the extended-spectrum beta-lactamase (ESBL) colonization status of each patient on every study day. Nosocomial transmission capacities (RA-values) for different species of MDR-GNB during study regimens will be quantified. As a secondary aim species-specific RA values will be compared between wards. Available data will be used to quantify incidences of cross-transmission in both study periods, using sophisticated modeling approaches. Investigators and the R-GNOSIS staff will make every attempt to collect complete data from all subjects enrolled in the study. Where possible, automatic extraction of data from hospital information systems will be used (without disclosing patient identifiers). There will be regular contact between the study coordinating centre and study sites to track and retrieve missing data. Should culture results be inadvertently lost, those data will be treated as missing at random. All inferential analyses will be based on available data. Details of the procedures for addressing missing cultures will be provided in the Statistical Analysis Plan. Details of the analysis methods and changes in the analyses from those described in the protocol will be documented in the statistical analysis plan prior to database lock. Those changes and the reasons for the changes will be described in detail in the final study report, but not presented to the regulation authorities or ethical committee as substantial amendments. Quality and safety assurance plan The quality of the study will be assured by two methods. 1. An external safety committee (SCom) consisting of three experts has the objective to guard the ecological safety during the study. During the intervention periods (CHX-Oro, SOD, SDD), the SCom will issue recommendations to continue or stop the study on a quarterly basis (three monthly), based on the results of monthly point prevalence cultures and input by participating ICUs. The primary safety measure to detect an increase of anti-microbial drug resistant bacteria is performing point prevalence cultures in all patients in the participating ICUs. The purpose of these cultures is to evaluate and ensure ecologic safety. Analysis will detect any multi-drug resistant gram negative bacteria (MDR-GNB), vancomycin resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) isolates. Also, susceptibility of /MDR-GNB to colistin, both used in SDD and SOD, will be tested. This way, any increase in the number of resistant isolates will be detected early. 2. Guidelines for reporting suspected unexpected serious adverse reactions (SUSAR's) have been developed. In ICU patients, co-morbidity and the natural history of the underlying critical illness can cause events which would meet the definition of (serious) adverse events. Given the natural occurrence of these events and the low risk for adverse drug reactions based on the broad experience with the current study medication, only the following adverse events will be recorded: 1. Adverse events possibly related to the medication (as judged by medical and scientific judgement) AND 2. Deemed serious by medical or scientific judgement (as judged by either the investigator of treating physician) AND 3. Not part of the natural history of the underlying critical illness Adverse events meeting these criteria should be reported by the local investigator within the following time limits:

- to the coordinating investigator within 24 hours

- to the accredited Institutional Review Boar (IRB) that has approved the protocol

in that country (within 7 days if the event is life-threatening or fatal, within 15 days if the event is not life-threatening or fatal)

- to the competent authority of that country (within 7 days if the event is

life-threatening or fatal, within 15 days if the event is not life-threatening or fatal) 3. A monitoring plan has been developed, in which: 1. The SPONSOR completes a central monitoring form for each participating hospital every three 3 months. This form registers for example the quality of transferred data, recruitment rate and the occurrence of site specific problems. 2. Each participating hospital completes a site self-monitoring form every three months. This form registers the completeness of the Investigator Site File, completeness of drug accountability and the correct reporting of suspected unexpected serious adverse reactions (SUSAR's).

Eligibility

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

Criteria:

Inclusion Criteria:

- mechanical ventilation (only invasive ventilation: i. e. intubated patients or

patients with tracheostomal ventilation)

- no planned extubation within 24 hours When mechanical ventilation is not started

directly after admission but later in the course of their ICU stay, patients are still eligible to participate. Exclusion Criteria:

- patients under the age of 18

- patients with known allergy to any of the medications or agents used (i. e. colistin,

tobramycin, nystatin or chlorhexidine )

- pregnancy

Participation ends as soon as the patient is extubated or after tracheostomal ventilation has stopped (weaning completed).

Locations and Contacts

Nienke L Plantinga, Drs., Phone: 0031 88 75 55102, Email: N.L.Plantinga@umcutrecht.nl

Universitair Ziekenhuis Antwerpen, Edegem B-2650, Belgium; Recruiting

Algemeen Ziekenhuis Sint Lucas, Gent 9000, Belgium; Recruiting

Universitair Ziekenhuis Gent, Gent 9000, Belgium; Recruiting

CHU Liege, Liege 4000, Belgium; Recruiting

Clinique Saint-Pierre Ottignies, Ottignies 340, Belgium; Recruiting

Ospedale San Camillo, Rome 00152, Italy; Recruiting

University clinic of respiratory and allergic diseases, Golnik 4204, Slovenia; Recruiting

Hospital Clinic of Barcelona, Barcelona 08036, Spain; Recruiting

l'Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain; Recruiting

Additional Information

Website of Consortium R-GNOSIS

Related publications:

de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, Bernards AT, Kuijper EJ, Joore JC, Leverstein-van Hall MA, Bindels AJ, Jansz AR, Wesselink RM, de Jongh BM, Dennesen PJ, van Asselt GJ, te Velde LF, Frenay IH, Kaasjager K, Bosch FH, van Iterson M, Thijsen SF, Kluge GH, Pauw W, de Vries JW, Kaan JA, Arends JP, Aarts LP, Sturm PD, Harinck HI, Voss A, Uijtendaal EV, Blok HE, Thieme Groen ES, Pouw ME, Kalkman CJ, Bonten MJ. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med. 2009 Jan 1;360(1):20-31. doi: 10.1056/NEJMoa0800394.

Edwards SJ, Braunholtz DA, Lilford RJ, Stevens AJ. Ethical issues in the design and conduct of cluster randomised controlled trials. BMJ. 1999 May 22;318(7195):1407-9. Review.

Starting date: December 2013
Last updated: May 27, 2015

Page last updated: August 23, 2015

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