<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02208154</url>
  </required_header>
  <id_info>
    <org_study_id>EudraCT 2012-002604-41</org_study_id>
    <nct_id>NCT02208154</nct_id>
  </id_info>
  <brief_title>Ecological Effects of Decolonisation Strategies in Intensive Care</brief_title>
  <acronym>RGNOSIS</acronym>
  <official_title>RGNOSIS: Ecological Effects of Decolonisation Strategies in Intensive Care</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MJM Bonten</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Paris 12 Val de Marne University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Previous research has shown that applying certain treatments can reduce both the number of&#xD;
      infections and the presence of resistant bacteria in the intensive care (ICU) and its&#xD;
      patients. These treatments have been used as standard care throughout the world for many&#xD;
      years, but they have not been compared to each other yet. The investigators aim to evaluate&#xD;
      the effect of 3 different treatments on the occurrence of resistant bacteria and bacterial&#xD;
      infections in the ICU and to establish which treatment is the best.&#xD;
&#xD;
      All adult patients undergoing mechanical ventilation are eligible for this study and will&#xD;
      receive treatment according to the study scheme. Twice weekly, sputum and rectal samples will&#xD;
      be obtained to measure the effects.&#xD;
&#xD;
      All ICU-patients will receive standard treatment, consisting of daily body washing with an&#xD;
      antiseptic (chlorhexidine 2%), oral care and a hand-hygiene program for health care workers&#xD;
      as endorsed by the WHO. According to 4 different study periods, each participant will receive&#xD;
      one of the following extra treatments depending on his or her admission date:&#xD;
&#xD;
        -  Standard treatment only (this is the control group)&#xD;
&#xD;
        -  Chlorhexidine 1% oral gel, this is an antiseptic.&#xD;
&#xD;
        -  Antibiotic mouth paste containing 3 different antibiotics (selective oropharyngeal&#xD;
           decontamination, SOD).&#xD;
&#xD;
        -  Antibiotic mouth paste and suspension for the stomach and intestines containing 3&#xD;
           different antibiotics (selective digestive decontamination, SDD).&#xD;
&#xD;
      All treatments will be given 4 times daily with the purpose of killing harmful bacteria in&#xD;
      the mouth (CHX, SOD,SDD) and digestive tract (SDD).&#xD;
&#xD;
      During the study the investigators will examine the effect of these treatments on:&#xD;
&#xD;
        -  the occurrence of blood stream infections with certain bacteria&#xD;
&#xD;
        -  cross-transmission of certain bacteria between patients&#xD;
&#xD;
        -  presence of these bacteria in the respiratory tract of the patients&#xD;
&#xD;
        -  patient survival&#xD;
&#xD;
      Benefits: Previous research has shown that these interventions can reduce infections in&#xD;
      intensive care patients.&#xD;
&#xD;
      Risks: The interventions performed (both cultures and treatment) are considered safe and are&#xD;
      already given as standard care in many ICUs throughout the world. There is a slight risk that&#xD;
      bacteria become resistant to antibiotics: this will be monitored closely during the trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction&#xD;
&#xD;
      The &quot;R-GNOSIS: Ecological Effects of Decolonization Strategies in Intensive Care&quot; study&#xD;
      assesses three decolonization interventions against standard care to evaluate unit wide&#xD;
      ecological effects and compare effectiveness.&#xD;
&#xD;
      Previous studies have demonstrated that decontamination interventions were beneficial to&#xD;
      individual patients but also influence ICU ecology, affecting patients who do not receive the&#xD;
      intervention. Decolonization with antibiotics have been shown to reduce the prevalence of&#xD;
      resistant bacteria during treatment [de Smet et al. NEJM 2009]. Reducing the presence of&#xD;
      these bacteria in some patients (that are decolonized), reduces cross transmission and is&#xD;
      therefore beneficial to all patients in the unit. The decolonization strategies therefore&#xD;
      represent an intensive care unit population rather than an individual patient intervention.&#xD;
      In this respect the study represents a cluster-cluster randomized clinical trial which&#xD;
      requires the intervention is undertaken on the whole ICU population [Edwards et al. BMJ&#xD;
      1999].&#xD;
&#xD;
      As decolonization strategies represent an ecological intervention on the whole critical care&#xD;
      population, all patients meeting inclusion/exclusion criteria will be entered into the study&#xD;
      according to ethics approval in each participating country. Each participating ICU will use&#xD;
      three decolonization strategies in a randomised order. The interventions are administered&#xD;
      four times daily to ventilated patients until extubation. The interventions will be compared&#xD;
      to a 6 month baseline period consisting of standard care only.&#xD;
&#xD;
      Standard operating procedures&#xD;
&#xD;
      Standard care&#xD;
&#xD;
      The baseline period is the first 6-month period and will be used to implement universal&#xD;
      &quot;standard care&quot;:&#xD;
&#xD;
        -  Chlorhexidine 2% body washings (CHX-BW) for all ICU patients. CHX-BW ensures state of&#xD;
           the art standard of care to prevent carriage and transmission of (resistant) gram&#xD;
           positive bacteria commonly residing on body surface, such as Staphylococcus aureus and&#xD;
           Enterococci.&#xD;
&#xD;
        -  A hand hygiene improvement program (HHIP) based on the program designed by the World&#xD;
           Health organisation (WHO). Implementation of the hand hygiene program derived from the&#xD;
           WHO hand hygiene program ensures state of the art standard of care for transmission&#xD;
           prevention of all relevant pathogens.&#xD;
&#xD;
        -  Standard oropharyngeal care consists of oral washing with sterile water (3-4 times&#xD;
           daily) and tooth brush twice daily.&#xD;
&#xD;
      &quot;Standard care&quot; will be the only protocolised intervention in the baseline period and will be&#xD;
      used throughout the entire study.&#xD;
&#xD;
      Intervention periods&#xD;
&#xD;
      After the baseline period, the first decolonization regimen will be implemented. The order of&#xD;
      regimens per ICU is decided by randomization. The three regimens are:&#xD;
&#xD;
        -  Chlorhexidine oral care (CHX-Oro) with chlorhexidine 1% oromucosal gel.&#xD;
&#xD;
        -  Selective oropharyngeal decontamination (SOD) with antibiotics. SOD consists of&#xD;
           application of a paste containing colistin, tobramycin in a 2% concentration and&#xD;
           nystatin 1 x 10^5 units.&#xD;
&#xD;
        -  Selective digestive decontamination (SDD), in which a 10 ml suspension via the&#xD;
           nasogastric tube containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u.&#xD;
           will be added to application of SOD paste.&#xD;
&#xD;
      All intervention periods last 6 months and all regimens are applied four times daily.&#xD;
&#xD;
      In contrast to some other SDD studies, systemic prophylaxis with Cefotaxime (or other broad&#xD;
      spectrum cephalosporins) will not be implemented as part of SDD.&#xD;
&#xD;
      Patient recruitment&#xD;
&#xD;
      All patients in the ICU receive standard care and minor anonymized personal data are&#xD;
      collected from them. Once monthly point prevalence cultures are collected from patients in&#xD;
      the ICU on that day.&#xD;
&#xD;
      Eligible patients in the ICU - in addition to the above mentioned - will receive one of the&#xD;
      interventions and will undergo surveillance sampling. More anonymized personal data are&#xD;
      collected (including some clinical culture results).&#xD;
&#xD;
      A waiver of informed consent is in place, but patients can opt out for data collection.&#xD;
&#xD;
      Culture sampling&#xD;
&#xD;
      Point prevalence cultures are taken once monthly from each patient present in the ICU at that&#xD;
      moment. These include a rectal swab and a respiratory sample and serve the purpose of&#xD;
      monitoring and evaluating ecological changes during all regimens.&#xD;
&#xD;
      Surveillance cultures are taken twice weekly from included patients and also include a rectal&#xD;
      swab and a respiratory sample. The samples are collected to measure the treatment effect.&#xD;
&#xD;
      Finally, results from regularly obtained cultures for clinical purposes (blood and&#xD;
      respiratory samples) will be recorded to measure the treatment effect.&#xD;
&#xD;
      Data-collection&#xD;
&#xD;
      Data-collection can be performed by two methods. All data will be &quot;anonymised&quot; by recoding&#xD;
      the patient identifier (ID) to a study patient ID and by removing their personal identifiers.&#xD;
&#xD;
        1. A web based electronic case report form (ECRF) has been designed within &quot;Research&#xD;
           Online&quot;. This system meets all requirements according to International Conference on&#xD;
           Harmonisation Good Clinical Practice (ICH-GCP)standards for electronic data entry with&#xD;
           respect to safeguarding data integrity and data security regulations.&#xD;
&#xD;
        2. Automatic extraction of data from electronic patient data dossiers may be performed if&#xD;
           technically possible without harming the patients' privacy.&#xD;
&#xD;
      Data dictionary&#xD;
&#xD;
        -  Data from all patients admitted to the ICU include sex, age, disease severity score,&#xD;
           admission/discharge date, mechanical ventilation (yes/no) and duration, ICU-survival.&#xD;
&#xD;
        -  Data from included patients additionally include: hospital admission date, place before&#xD;
           admission, reason for ICU admission, acute illness (yes/no), sites of organ failure,&#xD;
           antibiotic use on ICU-admission (yes/no), comorbidity, ventilation data, disposition at&#xD;
           28-days after ICU- admission, at ICU-discharge and at hospital-discharge, isolation&#xD;
           precautions.&#xD;
&#xD;
        -  Culture data include results from clinical respiratory and blood samples and&#xD;
           surveillance cultures from included patients and point prevalence cultures (monthly)&#xD;
           from all patients.&#xD;
&#xD;
        -  Ward-level antibiotic use will be recorded per study period.&#xD;
&#xD;
      Sample size calculation&#xD;
&#xD;
      In a Dutch SDD ICU trial the day-28 mortality rate during the baseline period was 27.5% (3).&#xD;
      Assuming a low level of cluster-effects, 2016 patients are needed in each phase to&#xD;
      demonstrate a 10% relative reduction in day-28 mortality as compared to Standard Care&#xD;
      (alpha=0.05; beta=0.8). We intend to include 2700 patients per arm. The margin of 600&#xD;
      patients per arm is included to allow for adjustment for differences in baseline&#xD;
      characteristics in a random-effects logistic regression model if needed, or to include&#xD;
      cluster-effects. Of note, assuming day-28 mortality in standard care to be 27%, the absolute&#xD;
      reduction that can be demonstrated is 2.7%. Day-28 mortality data will be derived from&#xD;
      clinical data obtained as part of routine standard care.&#xD;
&#xD;
      STATISTICAL ANALYSIS PLAN (updated October 2017)&#xD;
&#xD;
      INTRODUCTION.&#xD;
&#xD;
      Analysis will determine the effect of each intervention in the occurrence of bacteremia,&#xD;
      patient survival, colonization rates, and the use of antibiotics. Statistical analysis of the&#xD;
      primary objective and secondary objectives regarding mortality, bacteremia and ward-level&#xD;
      colonization with antibiotic resistant bacteria will account for ICU-level clustering and the&#xD;
      statistical methods used are described in detail in below. The use of antibiotics will be a&#xD;
      descriptive statistic.&#xD;
&#xD;
      All available data on patient colonization with MDR-GNB (both from screening and clinical&#xD;
      cultures) will be used to determine, as carefully as possible, the extended-spectrum&#xD;
      beta-lactamase (ESBL) colonization status of each patient on every study day. Nosocomial&#xD;
      transmission capacities (RA-values) for different species of MDR-GNB during study regimens&#xD;
      will be quantified. As a secondary aim species-specific RA values will be compared between&#xD;
      wards. Available data will be used to quantify incidences of cross-transmission in both study&#xD;
      periods, using sophisticated modeling approaches.&#xD;
&#xD;
      Investigators and the R-GNOSIS staff will make every attempt to collect complete data from&#xD;
      all subjects enrolled in the study. Where possible, automatic extraction of data from&#xD;
      hospital information systems will be used (without disclosing patient identifiers). There&#xD;
      will be regular contact between the study coordinating centre and study sites to track and&#xD;
      retrieve missing data. Should culture results be inadvertently lost, those data will be&#xD;
      treated as missing at random. All inferential analyses will be based on available data.&#xD;
&#xD;
      The detailed statistical analysis plan has been established prior to database lock and is&#xD;
      divided into two parts.&#xD;
&#xD;
      PART 1: Clinical outcomes (patient data)&#xD;
&#xD;
      The data&#xD;
&#xD;
      The data analysis will be performed on all patients included during the baseline period, the&#xD;
      last 2 weeks of the wash-out/in periods and those included during one of the three&#xD;
      intervention periods. Two ICU admissions of the same patient with less than 3 days in between&#xD;
      will be merged and analyzed as one ICU admission.&#xD;
&#xD;
      The following cohorts will be made for analysis of the following clinical outcomes:&#xD;
&#xD;
        1. Cohort &quot;ICU-admissions&quot;: ICU-acquired bacteremia, ICU survival.&#xD;
&#xD;
        2. Cohort &quot;Hospital-admissions&quot;: Hospital survival&#xD;
&#xD;
        3. Cohort &quot;first ICU-admissions&quot;, excluding re-admissions to the ICU within 30 days after&#xD;
           prior ICU-discharge: 28-day survival&#xD;
&#xD;
      Missing data.&#xD;
&#xD;
      Missing data will be retrieved where possible, after which a complete case analysis will be&#xD;
      performed.&#xD;
&#xD;
      Statistical models.&#xD;
&#xD;
      To adjust for potential selection bias in this cluster randomized trials with crossover&#xD;
      (without blinding), the statistical analysis will be performed using doubly robust&#xD;
      estimation. [Funk MJ et al. Am J Epidemiol 2011]&#xD;
&#xD;
      Propensity score model.&#xD;
&#xD;
      The propensity score model will include the following a priori selected confounders:&#xD;
&#xD;
        -  Age&#xD;
&#xD;
        -  Gender&#xD;
&#xD;
        -  Disease severity (either APACHE II or SAPS II score)&#xD;
&#xD;
        -  Use of antibiotics upon ICU-admission&#xD;
&#xD;
        -  Prior location before ICU-admission&#xD;
&#xD;
        -  Admission type (medical/surgical/trauma)&#xD;
&#xD;
        -  Charlson comorbidity score&#xD;
&#xD;
        -  Hospital of recruitment (hospital) As two different scoring methods , APACHE II or SAPS&#xD;
           II, have been used to determine disease severity by different hospitals, two separate&#xD;
           propensity score models will be fitted (one for hospitals that recorded APACHE II and&#xD;
           one for hospitals that recorded SAPS II).&#xD;
&#xD;
      These propensity score models will be fitted in the cohort &quot;ICU-admissions&quot; using the&#xD;
      R-package 'twang'. [McCaffrey Stat Med. 2013] This package uses generalized boosted models&#xD;
      machine learning techniques to calculate weights for each patient. The resulting weights&#xD;
      represent the inverse probability for a patient to be included in the baseline, CHX, SOD or&#xD;
      SDD arm and will be used to weigh the data in the outcome models , creating&#xD;
      pseudo-populations with an equal distribution of the specified covariates over treatment&#xD;
      groups.&#xD;
&#xD;
      Outcome models.&#xD;
&#xD;
      Separate models will be fitted per endpoint, as specified in table 1. All models will include&#xD;
      the inverse probability weights, the confounders included in the propensity score model and&#xD;
      the mean hand hygiene compliance per study period per hospital (hand hygiene compliance might&#xD;
      differ per study period and act as a confounder on all outcomes) to obtain doubly robust&#xD;
      estimators. A dummy variable indicating the measure of disease severity (APACHE II or SAPS&#xD;
      II) will be included as an interaction with the standardized disease severity to overcome&#xD;
      different hospital having registered different measures. In addition, two levels of&#xD;
      clustering will be taken into account, as follows:&#xD;
&#xD;
        -  Hospital of recruitment: fixed effect, acknowledging that the risk of the outcome&#xD;
           differs per hospital&#xD;
&#xD;
        -  Cluster period (i.e. periods 1-4 per hospital): random intercept, acknowledging that&#xD;
           patients recruited in different periods within hospitals may be more alike with regard&#xD;
           to the risk of the outcome.&#xD;
&#xD;
      Table 1. Outcome models per endpoint&#xD;
&#xD;
        -  ICU-acquired bacteremia Model: Cox proportional hazard (hazard ratio) Competing&#xD;
           endpoints: ICU discharge, death in ICU&#xD;
&#xD;
        -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:&#xD;
           ICU-discharge&#xD;
&#xD;
        -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:&#xD;
           hospital-discharge&#xD;
&#xD;
        -  28-day survival Model: generalized linear model (odds ratio) Family: (quasi)binominal&#xD;
           Link: logit&#xD;
&#xD;
      Results will be presented as hazard ratios or odds ratios with 95%-CI. R and STATA will be&#xD;
      used to perform the analyses specified above.&#xD;
&#xD;
      Sensitivity analysis.&#xD;
&#xD;
      As eligibility in this open cluster-randomized study was defined as &quot;Expected length of MV&#xD;
      &gt;24h&quot;, selection bias may have occurred (as discussed under 'confounding adjustment'). To&#xD;
      quantify this potential bias a sensitivity analysis will be performed in which patients who&#xD;
      left the ICU within 2 days after study inclusion are excluded, as these patients could not&#xD;
      reach the ICU-acquired bacteremia primary endpoint (which requires at least three days in&#xD;
      ICU).&#xD;
&#xD;
      Exploratory analysis.&#xD;
&#xD;
      As an exploratory analysis the treatment effect on 28-day survival and ICU-acquired&#xD;
      bacteremia per ICU will be visualized in Forest plots, in which ICUs are ranked on the&#xD;
      prevalence of bacteremia with highly resistant micro-organisms (HRMO) during the baseline&#xD;
      period.&#xD;
&#xD;
      PART 2: Antibiotic resistance (ward level data)&#xD;
&#xD;
      The data.&#xD;
&#xD;
      The monthly point prevalence screenings on both included and non-included patients will be&#xD;
      analyzed on two levels, each including outcomes for individual HRMO (e.g. carbapenem&#xD;
      resistant GNB, MRSA, etc.) and the aggregate &quot;any HRMO&quot;.&#xD;
&#xD;
        1. Cohort &quot;respiratory tract&quot;&#xD;
&#xD;
        2. Cohort &quot;digestive tract&quot;&#xD;
&#xD;
      Missing data.&#xD;
&#xD;
      If a patient or tractus was not sampled, it will be excluded from the analysis (and the&#xD;
      denominator). If an antibiotic susceptibility result was missing, the highest susceptibility&#xD;
      result from the same species in the same tractus 7 days prior or after the point prevalence&#xD;
      date was &quot;imputed&quot;, if available. Completeness of susceptibility testing will be reported as&#xD;
      a descriptive statistic.&#xD;
&#xD;
      Since monthly point prevalence measurements are taken on fixed days (i.e. first Monday,&#xD;
      occasional exceptions accepted) on all patients present in the ward (both included and&#xD;
      non-included) we do not expect bias due to selective inclusion per study period (as in the&#xD;
      analysis of the clinical outcomes).&#xD;
&#xD;
      Final models.&#xD;
&#xD;
      We will perform logistic regression analyses with a log-link for each endpoint and include&#xD;
      terms for underlying time-trend per hospital (months since study start * hospital) and&#xD;
      time-trend per intervention (months since start study period * study period) and correct for&#xD;
      repeated measurements on the same patient (corrected standard errors with sandwich&#xD;
      estimator). Results will be presented as risk ratio's with 95%-CI.&#xD;
&#xD;
      Quality and safety assurance plan&#xD;
&#xD;
      The quality of the study will be assured by two methods.&#xD;
&#xD;
        1. An external safety committee (SCom) consisting of three experts has the objective to&#xD;
           guard the ecological safety during the study. During the intervention periods (CHX-Oro,&#xD;
           SOD, SDD), the SCom will issue recommendations to continue or stop the study on a&#xD;
           quarterly basis (three monthly), based on the results of monthly point prevalence&#xD;
           cultures and input by participating ICUs.&#xD;
&#xD;
           The primary safety measure to detect an increase of anti-microbial drug resistant&#xD;
           bacteria is performing point prevalence cultures in all patients in the participating&#xD;
           ICUs. The purpose of these cultures is to evaluate and ensure ecologic safety. Analysis&#xD;
           will detect any multi-drug resistant gram negative bacteria (MDR-GNB), vancomycin&#xD;
           resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA)&#xD;
           isolates. Also, susceptibility of /MDR-GNB to colistin, both used in SDD and SOD, will&#xD;
           be tested. This way, any increase in the number of resistant isolates will be detected&#xD;
           early.&#xD;
&#xD;
        2. Guidelines for reporting suspected unexpected serious adverse reactions (SUSAR's) have&#xD;
           been developed. In ICU patients, co-morbidity and the natural history of the underlying&#xD;
           critical illness can cause events which would meet the definition of (serious) adverse&#xD;
           events. Given the natural occurrence of these events and the low risk for adverse drug&#xD;
           reactions based on the broad experience with the current study medication, only the&#xD;
           following adverse events will be recorded:&#xD;
&#xD;
             1. Adverse events possibly related to the medication (as judged by medical and&#xD;
                scientific judgement) AND&#xD;
&#xD;
             2. Deemed serious by medical or scientific judgement (as judged by either the&#xD;
                investigator of treating physician) AND&#xD;
&#xD;
             3. Not part of the natural history of the underlying critical illness&#xD;
&#xD;
           Adverse events meeting these criteria should be reported by the local investigator&#xD;
           within the following time limits:&#xD;
&#xD;
             -  to the coordinating investigator within 24 hours&#xD;
&#xD;
             -  to the accredited Institutional Review Boar (IRB) that has approved the protocol in&#xD;
                that country (within 7 days if the event is life-threatening or fatal, within 15&#xD;
                days if the event is not life-threatening or fatal)&#xD;
&#xD;
             -  to the competent authority of that country (within 7 days if the event is&#xD;
                life-threatening or fatal, within 15 days if the event is not life-threatening or&#xD;
                fatal)&#xD;
&#xD;
        3. A monitoring plan has been developed, in which:&#xD;
&#xD;
             1. The SPONSOR completes a central monitoring form for each participating hospital&#xD;
                every three 3 months. This form registers for example the quality of transferred&#xD;
                data, recruitment rate and the occurrence of site specific problems.&#xD;
&#xD;
             2. Each participating hospital completes a site self-monitoring form every three&#xD;
                months. This form registers the completeness of the Investigator Site File,&#xD;
                completeness of drug accountability and the correct reporting of suspected&#xD;
                unexpected serious adverse reactions (SUSAR's).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2013</start_date>
  <completion_date type="Actual">October 27, 2017</completion_date>
  <primary_completion_date type="Actual">October 27, 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>This study is a cluster-randomized multicenter study with crossover of interventions within study centers. The first study period is always the baseline period. After six months, the first intervention period (order is determined by randomization) is implemented, followed by the second and third intervention. The intervention periods are separated by a wash out period of one month.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ICU-Ecology</measure>
    <time_frame>27 months</time_frame>
    <description>To determine the ecological effects of decolonisation regimens (SDD, SOD and CHX-Oro) in reducing (MDR-GNB) ICU-acquired bacteraemia when compared to standard care.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cross-transmission rates</measure>
    <time_frame>27 months</time_frame>
    <description>To quantify cross-transmission rates with MDR-GNB during 3 decolonisation regimens and during standard care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory tract colonization</measure>
    <time_frame>27 months</time_frame>
    <description>To determine the effectiveness of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in reducing acquired respiratory tract colonisation with MDR-GNB when compared to standard care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ward-level systemic antibiotic use</measure>
    <time_frame>27 months</time_frame>
    <description>To quantify the effects of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in ICU patients on overall systemic antibiotic use when compared to standard care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>colonization in relation to bacteraemia</measure>
    <time_frame>27 months</time_frame>
    <description>To quantify on ICU level the associations between intestinal and respiratory tract colonisation with GNB and the occurrence of ICU-acquired GNB bacteraemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>transmission capacities of different bacteria</measure>
    <time_frame>27 months</time_frame>
    <description>To quantify species-specific nosocomial transmission capacities (reproductive number per hospital admission, RA) of MDR-GNB during 3 decolonisation regimens and during standard care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient survival</measure>
    <time_frame>27 months</time_frame>
    <description>To determine the effectiveness of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in reducing day-28 and in hospital mortality when compared to standard care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bacteraemia with resistant bacteria</measure>
    <time_frame>27 months</time_frame>
    <description>To determine ICU-acquired bacteraemia rates caused by any multi-drug resistant micro-organism, including MRSA, VRE, MDR-GNB, Acinetobacter, S. maltophilia, and ceftazidime- and/or carbapenem resistant P. aeruginosa, during each phase of the study.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">8665</enrollment>
  <condition>ICU-ecology (Multidrug Resistant Bacteria)</condition>
  <condition>ICU-acquired Bacteraemia</condition>
  <arm_group>
    <arm_group_label>Standard care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard infection prevention measurements will be implemented before the baseline period and carried out throughout the entire trial. They consist of:&#xD;
Chlorhexidine 2% body washings (CHX-BW) for all ICU patients. The face and neck of the patient will not be cleansed with Chlorhexidine to prevent irritation of the eyes and face.&#xD;
A hand hygiene improvement program (HHIP) based on the program designed by the World Health organisation (WHO).&#xD;
Standard oropharyngeal care consists of oral washing with sterile water (3-4 times daily) and tooth brush twice daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chlorhexidine oral care (CHX-Oro)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Chlorhexidine digluconate oromucosal gel 1%, 2cm, to be administered 4 times daily, during invasive mechanical ventilation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Selective oropharyngeal decontamination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Selective oropharyngeal decontamination (SOD) mouth paste containing colistin and tobramycin in a 2% concentration and nystatin 1 x 10^5 units, dosage 0.5g , to be administered 4 times daily during the entire period of invasive mechanical ventilation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Selective digestive decontamination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Selective digestive decontamination (SDD), suspension via the nasogastric tube containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u., dosage 10ml, to be administered together with SOD (see above) 4 times daily during entire period of mechanical ventilation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chlorhexidine oral care (CHX-Oro)</intervention_name>
    <description>Oromucosal gel consisting of chlorhexidine 1%, administered 4 times daily.</description>
    <arm_group_label>Chlorhexidine oral care (CHX-Oro)</arm_group_label>
    <arm_group_label>Standard care</arm_group_label>
    <other_name>Chlorhexidine digluconate</other_name>
    <other_name>CHX-Oro</other_name>
    <other_name>Chlorhexidine 1% oromucosal gel</other_name>
    <other_name>Corsodyl dental gel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Selective oropharyngeal decontamination (SOD)</intervention_name>
    <description>SOD consists of application of a paste containing colistin, tobramycin in a 2% concentration and nystatin 1 x 10^5 units. SOD will be applied to the mouth 4 times daily until extubation.</description>
    <arm_group_label>Selective oropharyngeal decontamination</arm_group_label>
    <arm_group_label>Standard care</arm_group_label>
    <other_name>SOD</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Selective Digestive Decontamination (SDD)</intervention_name>
    <description>SDD consists of both:&#xD;
SOD (described elsewhere)&#xD;
AND 10 ml of an enteric suspension containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u, to be administered via the nasogastric tube.&#xD;
The combination is administered 4 times daily (Unlike in previous studies, systemic antibiotics are not a part of SDD)</description>
    <arm_group_label>Selective digestive decontamination</arm_group_label>
    <arm_group_label>Standard care</arm_group_label>
    <other_name>SDD</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  mechanical ventilation (only invasive ventilation: i.e. intubated patients or patients&#xD;
             with tracheostomal ventilation)&#xD;
&#xD;
          -  no planned extubation within 24 hours When mechanical ventilation is not started&#xD;
             directly after admission but later in the course of their ICU stay, patients are still&#xD;
             eligible to participate.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patients under the age of 18&#xD;
&#xD;
          -  patients with known allergy to any of the medications or agents used (i.e. colistin,&#xD;
             tobramycin, nystatin or chlorhexidine )&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
        Participation ends as soon as the patient is extubated or after tracheostomal ventilation&#xD;
        has stopped (weaning completed).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marc JM Bonten, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Christian Brun-Buisson, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>UPEC Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Universitair Ziekenhuis Antwerpen</name>
      <address>
        <city>Edegem</city>
        <zip>B-2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Algemeen Ziekenhuis Sint Lucas</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitair Ziekenhuis Gent</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Liege</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique Saint-Pierre Ottignies</name>
      <address>
        <city>Ottignies</city>
        <zip>340</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale San Camillo</name>
      <address>
        <city>Rome</city>
        <zip>00152</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Geral de Santo António (Centro Hospitalar do Porto, EPE)</name>
      <address>
        <city>Porto</city>
        <zip>4099-001</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE</name>
      <address>
        <city>Vila Real</city>
        <zip>5000 - 508</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University clinic of respiratory and allergic diseases</name>
      <address>
        <city>Golnik</city>
        <zip>4204</zip>
        <country>Slovenia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinic of Barcelona</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>l'Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario y Politécnico La Fé de Valencia</name>
      <address>
        <city>Valencia</city>
        <zip>46026</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Wales</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Italy</country>
    <country>Portugal</country>
    <country>Slovenia</country>
    <country>Spain</country>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.r-gnosis.eu/</url>
    <description>Website of Consortium R-GNOSIS</description>
  </link>
  <reference>
    <citation>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.</citation>
    <PMID>19118302</PMID>
  </reference>
  <reference>
    <citation>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. doi: 10.1136/bmj.318.7195.1407. No abstract available.</citation>
    <PMID>10334756</PMID>
  </reference>
  <reference>
    <citation>Funk MJ, Westreich D, Wiesen C, Sturmer T, Brookhart MA, Davidian M. Doubly robust estimation of causal effects. Am J Epidemiol. 2011 Apr 1;173(7):761-7. doi: 10.1093/aje/kwq439. Epub 2011 Mar 8.</citation>
    <PMID>21385832</PMID>
  </reference>
  <reference>
    <citation>McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013 Aug 30;32(19):3388-414. doi: 10.1002/sim.5753. Epub 2013 Mar 18.</citation>
    <PMID>23508673</PMID>
  </reference>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>July 31, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 4, 2014</study_first_posted>
  <last_update_submitted>October 30, 2017</last_update_submitted>
  <last_update_submitted_qc>October 30, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>MJM Bonten</investigator_full_name>
    <investigator_title>Professor of Molecular Epidemiology of Infectious Diseases</investigator_title>
  </responsible_party>
  <keyword>ICU acquired bacteraemia</keyword>
  <keyword>colonization</keyword>
  <keyword>decolonization</keyword>
  <keyword>selective decontamination</keyword>
  <keyword>multidrug resistant bacteria</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bacteremia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chlorhexidine</mesh_term>
    <mesh_term>Chlorhexidine gluconate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02208154
org study id: EudraCT 2012-002604-41
nct id: NCT02208154
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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 (updated October 2017)

      INTRODUCTION.

      Analysis will determine the effect of each intervention in the occurrence of bacteremia,
      patient survival, colonization rates, and the use of antibiotics. Statistical analysis of the
      primary objective and secondary objectives regarding mortality, bacteremia and ward-level
      colonization with antibiotic resistant bacteria will account for ICU-level clustering and the
      statistical methods used are described in detail in below. The use of antibiotics will be a
      descriptive statistic.

      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.

      The detailed statistical analysis plan has been established prior to database lock and is
      divided into two parts.

      PART 1: Clinical outcomes (patient data)

      The data

      The data analysis will be performed on all patients included during the baseline period, the
      last 2 weeks of the wash-out/in periods and those included during one of the three
      intervention periods. Two ICU admissions of the same patient with less than 3 days in between
      will be merged and analyzed as one ICU admission.

      The following cohorts will be made for analysis of the following clinical outcomes:

        1. Cohort "ICU-admissions": ICU-acquired bacteremia, ICU survival.

        2. Cohort "Hospital-admissions": Hospital survival

        3. Cohort "first ICU-admissions", excluding re-admissions to the ICU within 30 days after
           prior ICU-discharge: 28-day survival

      Missing data.

      Missing data will be retrieved where possible, after which a complete case analysis will be
      performed.

      Statistical models.

      To adjust for potential selection bias in this cluster randomized trials with crossover
      (without blinding), the statistical analysis will be performed using doubly robust
      estimation. [Funk MJ et al. Am J Epidemiol 2011]

      Propensity score model.

      The propensity score model will include the following a priori selected confounders:

        -  Age

        -  Gender

        -  Disease severity (either APACHE II or SAPS II score)

        -  Use of antibiotics upon ICU-admission

        -  Prior location before ICU-admission

        -  Admission type (medical/surgical/trauma)

        -  Charlson comorbidity score

        -  Hospital of recruitment (hospital) As two different scoring methods , APACHE II or SAPS
           II, have been used to determine disease severity by different hospitals, two separate
           propensity score models will be fitted (one for hospitals that recorded APACHE II and
           one for hospitals that recorded SAPS II).

      These propensity score models will be fitted in the cohort "ICU-admissions" using the
      R-package 'twang'. [McCaffrey Stat Med. 2013] This package uses generalized boosted models
      machine learning techniques to calculate weights for each patient. The resulting weights
      represent the inverse probability for a patient to be included in the baseline, CHX, SOD or
      SDD arm and will be used to weigh the data in the outcome models , creating
      pseudo-populations with an equal distribution of the specified covariates over treatment
      groups.

      Outcome models.

      Separate models will be fitted per endpoint, as specified in table 1. All models will include
      the inverse probability weights, the confounders included in the propensity score model and
      the mean hand hygiene compliance per study period per hospital (hand hygiene compliance might
      differ per study period and act as a confounder on all outcomes) to obtain doubly robust
      estimators. A dummy variable indicating the measure of disease severity (APACHE II or SAPS
      II) will be included as an interaction with the standardized disease severity to overcome
      different hospital having registered different measures. In addition, two levels of
      clustering will be taken into account, as follows:

        -  Hospital of recruitment: fixed effect, acknowledging that the risk of the outcome
           differs per hospital

        -  Cluster period (i.e. periods 1-4 per hospital): random intercept, acknowledging that
           patients recruited in different periods within hospitals may be more alike with regard
           to the risk of the outcome.

      Table 1. Outcome models per endpoint

        -  ICU-acquired bacteremia Model: Cox proportional hazard (hazard ratio) Competing
           endpoints: ICU discharge, death in ICU

        -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:
           ICU-discharge

        -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:
           hospital-discharge

        -  28-day survival Model: generalized linear model (odds ratio) Family: (quasi)binominal
           Link: logit

      Results will be presented as hazard ratios or odds ratios with 95%-CI. R and STATA will be
      used to perform the analyses specified above.

      Sensitivity analysis.

      As eligibility in this open cluster-randomized study was defined as "Expected length of MV
      >24h", selection bias may have occurred (as discussed under 'confounding adjustment'). To
      quantify this potential bias a sensitivity analysis will be performed in which patients who
      left the ICU within 2 days after study inclusion are excluded, as these patients could not
      reach the ICU-acquired bacteremia primary endpoint (which requires at least three days in
      ICU).

      Exploratory analysis.

      As an exploratory analysis the treatment effect on 28-day survival and ICU-acquired
      bacteremia per ICU will be visualized in Forest plots, in which ICUs are ranked on the
      prevalence of bacteremia with highly resistant micro-organisms (HRMO) during the baseline
      period.

      PART 2: Antibiotic resistance (ward level data)

      The data.

      The monthly point prevalence screenings on both included and non-included patients will be
      analyzed on two levels, each including outcomes for individual HRMO (e.g. carbapenem
      resistant GNB, MRSA, etc.) and the aggregate "any HRMO".

        1. Cohort "respiratory tract"

        2. Cohort "digestive tract"

      Missing data.

      If a patient or tractus was not sampled, it will be excluded from the analysis (and the
      denominator). If an antibiotic susceptibility result was missing, the highest susceptibility
      result from the same species in the same tractus 7 days prior or after the point prevalence
      date was "imputed", if available. Completeness of susceptibility testing will be reported as
      a descriptive statistic.

      Since monthly point prevalence measurements are taken on fixed days (i.e. first Monday,
      occasional exceptions accepted) on all patients present in the ward (both included and
      non-included) we do not expect bias due to selective inclusion per study period (as in the
      analysis of the clinical outcomes).

      Final models.

      We will perform logistic regression analyses with a log-link for each endpoint and include
      terms for underlying time-trend per hospital (months since study start * hospital) and
      time-trend per intervention (months since start study period * study period) and correct for
      repeated measurements on the same patient (corrected standard errors with sandwich
      estimator). Results will be presented as risk ratio's with 95%-CI.

      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).
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: This study is a cluster-randomized multicenter study with crossover of interventions within study centers. The first study period is always the baseline period. After six months, the first intervention period (order is determined by randomization) is implemented, followed by the second and third intervention. The intervention periods are separated by a wash out period of one month.
primary purpose: Prevention
masking: None (Open Label)
measure: ICU-Ecology
time frame: 27 months
description: To determine the ecological effects of decolonisation regimens (SDD, SOD and CHX-Oro) in reducing (MDR-GNB) ICU-acquired bacteraemia when compared to standard care.
measure: Cross-transmission rates
time frame: 27 months
description: To quantify cross-transmission rates with MDR-GNB during 3 decolonisation regimens and during standard care.
measure: Respiratory tract colonization
time frame: 27 months
description: To determine the effectiveness of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in reducing acquired respiratory tract colonisation with MDR-GNB when compared to standard care.
measure: ward-level systemic antibiotic use
time frame: 27 months
description: To quantify the effects of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in ICU patients on overall systemic antibiotic use when compared to standard care.
measure: colonization in relation to bacteraemia
time frame: 27 months
description: To quantify on ICU level the associations between intestinal and respiratory tract colonisation with GNB and the occurrence of ICU-acquired GNB bacteraemia.
measure: transmission capacities of different bacteria
time frame: 27 months
description: To quantify species-specific nosocomial transmission capacities (reproductive number per hospital admission, RA) of MDR-GNB during 3 decolonisation regimens and during standard care.
measure: Patient survival
time frame: 27 months
description: To determine the effectiveness of 3 decolonisation regimens (SDD, SOD and CHX-Oro) in reducing day-28 and in hospital mortality when compared to standard care.
measure: bacteraemia with resistant bacteria
time frame: 27 months
description: To determine ICU-acquired bacteraemia rates caused by any multi-drug resistant micro-organism, including MRSA, VRE, MDR-GNB, Acinetobacter, S. maltophilia, and ceftazidime- and/or carbapenem resistant P. aeruginosa, during each phase of the study.
arm group label: Standard care
arm group type: Active Comparator
description: Standard infection prevention measurements will be implemented before the baseline period and carried out throughout the entire trial. They consist of:
Chlorhexidine 2% body washings (CHX-BW) for all ICU patients. The face and neck of the patient will not be cleansed with Chlorhexidine to prevent irritation of the eyes and face.
A hand hygiene improvement program (HHIP) based on the program designed by the World Health organisation (WHO).
Standard oropharyngeal care consists of oral washing with sterile water (3-4 times daily) and tooth brush twice daily.
arm group label: Chlorhexidine oral care (CHX-Oro)
arm group type: Experimental
description: Chlorhexidine digluconate oromucosal gel 1%, 2cm, to be administered 4 times daily, during invasive mechanical ventilation.
arm group label: Selective oropharyngeal decontamination
arm group type: Experimental
description: Selective oropharyngeal decontamination (SOD) mouth paste containing colistin and tobramycin in a 2% concentration and nystatin 1 x 10^5 units, dosage 0.5g , to be administered 4 times daily during the entire period of invasive mechanical ventilation.
arm group label: Selective digestive decontamination
arm group type: Experimental
description: Selective digestive decontamination (SDD), suspension via the nasogastric tube containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u., dosage 10ml, to be administered together with SOD (see above) 4 times daily during entire period of mechanical ventilation.
intervention type: Drug
intervention name: Chlorhexidine oral care (CHX-Oro)
description: Oromucosal gel consisting of chlorhexidine 1%, administered 4 times daily.
arm group label: Chlorhexidine oral care (CHX-Oro)
arm group label: Standard care
other name: Chlorhexidine digluconate
other name: CHX-Oro
other name: Chlorhexidine 1% oromucosal gel
other name: Corsodyl dental gel
intervention type: Drug
intervention name: Selective oropharyngeal decontamination (SOD)
description: SOD consists of application of a paste containing colistin, tobramycin in a 2% concentration and nystatin 1 x 10^5 units. SOD will be applied to the mouth 4 times daily until extubation.
arm group label: Selective oropharyngeal decontamination
arm group label: Standard care
other name: SOD
intervention type: Drug
intervention name: Selective Digestive Decontamination (SDD)
description: SDD consists of both:
SOD (described elsewhere)
AND 10 ml of an enteric suspension containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u, to be administered via the nasogastric tube.
The combination is administered 4 times daily (Unlike in previous studies, systemic antibiotics are not a part of SDD)
arm group label: Selective digestive decontamination
arm group label: Standard care
other name: SDD
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marc JM Bonten, Prof.
role: Principal Investigator
affiliation: UMC Utrecht
last name: Christian Brun-Buisson, Prof.
role: Principal Investigator
affiliation: UPEC Paris
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: Italy
country: Portugal
country: Slovenia
country: Spain
country: United Kingdom
url: http://www.r-gnosis.eu/
description: Website of Consortium R-GNOSIS
citation: 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.
PMID: 19118302
citation: 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. doi: 10.1136/bmj.318.7195.1407. No abstract available.
PMID: 10334756
citation: Funk MJ, Westreich D, Wiesen C, Sturmer T, Brookhart MA, Davidian M. Doubly robust estimation of causal effects. Am J Epidemiol. 2011 Apr 1;173(7):761-7. doi: 10.1093/aje/kwq439. Epub 2011 Mar 8.
PMID: 21385832
citation: McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013 Aug 30;32(19):3388-414. doi: 10.1002/sim.5753. Epub 2013 Mar 18.
PMID: 23508673
responsible party type: Sponsor-Investigator
investigator affiliation: UMC Utrecht
investigator full name: MJM Bonten
investigator title: Professor of Molecular Epidemiology of Infectious Diseases
mesh term: Bacteremia
mesh term: Chlorhexidine
mesh term: Chlorhexidine gluconate