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Impact of the Duration of Antibiotics on Clinical Events in Patients With Pseudomonas Aeruginosa Ventilator-associated Pneumonia (iDIAPASON) (iDIAPASON)

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ClinicalTrials.gov Identifier: NCT02634411
Recruitment Status : Unknown
Verified August 2016 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was:  Recruiting
First Posted : December 18, 2015
Last Update Posted : August 24, 2016
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE November 19, 2015
First Posted Date  ICMJE December 18, 2015
Last Update Posted Date August 24, 2016
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 15, 2015)
A composite endpoint of morbi-mortality combining Day-90 mortality and PA-VAP recurrence rate during hospitalization in the ICU (within 90 days). [ Time Frame: 90 days after effective antibiotherapy ]
A composite endpoint combining Day-90 mortality and PA-VAP recurrence rate during hospitalization in the ICU (within 90 days). Recurrence will be defined a posteriori by 3 independent experts with predefined criteria: clinical suspicion of VAP (≥ two criteria including: fever> 38.5 ° C, leukocytosis > 109/L or leukopenia < 4.108/L, purulent tracheobronchial secretions and a new or persistent infiltrate on chest radiography) associated with a positive quantitative culture of a respiratory sample (bronchoalveolar lavage fluid (significant threshold ≥104 colony-forming units/mL) or plugged telescopic catheter (significant threshold ≥103 colony-forming units/mL) or quantitative endotracheal aspirate distal pulmonary secretion samples (significant threshold ≥106 colony-forming units/mL)).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02634411 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 15, 2015)
  • Measure of mortality rate (%) in the ICU [ Time Frame: Day 30 and Day 90 after effective antibiotherapy ]
  • Measure of morbidity in ICU by duration of mechanical ventilation (days) [ Time Frame: Day 30 and Day 90 after effective antibiotherapy ]
  • Measure of morbidity in ICU by duration of hospitalization in ICU (days) [ Time Frame: Day 30 and Day 90 after effective antibiotherapy ]
  • Acquisition of MDR during the hospitalization in the ICU. [ Time Frame: during stay in the ICU : up to 90 days ]
  • Exposure to antibiotics during the hospitalization in the ICU (days) [ Time Frame: during stay in the ICU : up to 90 days ]
  • Number of extrapulmonary infections during the hospitalization in the ICU [ Time Frame: during stay in the ICU : up to 90 days ]
  • Type of extrapulmonary infections during the hospitalization in the ICU [ Time Frame: during stay in the ICU : up to 90 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of the Duration of Antibiotics on Clinical Events in Patients With Pseudomonas Aeruginosa Ventilator-associated Pneumonia (iDIAPASON)
Official Title  ICMJE Impact of the Duration of Antibiotics on Clinical Events in Patients With Pseudomonas Aeruginosa Ventilator-associated Pneumonia : a Randomized Controlled Study (iDIAPASON)
Brief Summary

Ventilator-associated pneumonia (VAP) accounts for 25% of infections in intensive care units (Réseau RAISIN 2012). A short duration (8 days; SD) vs. long duration (15 days; LD) of antibiotic therapy has a comparable clinical efficacy with less antibiotic use and less multidrug-resistant pathogens (MDR) emergence. These results have led the American Thoracic Society to recommend SD therapy for VAP, with the exception of documented VAP of non-fermenting Gram negative bacilli (NF-GNB), including Pseudomonas aeruginosa (PA-VAP), due to the absence of studies focusing specifically on PA-VAP. Thus the beneficial effect of SD therapy in PA-VAP is still a matter of debate. In a small (n=127) subgroup analysis, a higher rate of recurrence with SD therapy (n=21, 32.8%) has been observed compared with LD therapy group (n=12, 19.0%). Unfortunately, the definition of recurrence was essentially based on microbiological rather than clinical data, and the higher rate of recurrence observed could rather reflect a higher rate of colonization more than a new infection.

Interestingly, a trend for a lower rate of mortality was also observed in the SD group (n=15, 23.4%) compared with the LD group (n=19, 30.2%), but this study was clearly underpowered to detect a difference of mortality between groups.

The two strategies were considered as not different, for the risk of mortality in a recent meta-analysis, performed on the very few available studies (n=2), that (OR = 1.33, 95% CI [0.33 to 5.26] for SD vs. LD strategies respectively). However, this conclusion remains questionable considering the large confidence interval of the risk and the power of these studies.

Primary objective and assessment criterion: To assess the non-inferiority of a short duration of antibiotics (8 days) vs. prolonged antibiotic therapy (15 days) in P. aeruginosa ventilator-associated pneumonia (PA-VAP) on a composite end-point combining Day-90 mortality and PA-VAP recurrence rate during hospitalization in the ICU.

Study Design :

Randomized, open-labeled non inferiority controlled trial 32 French Intensive Care Units participating to the study

Research period:

Total study duration: 27 months Inclusion period: 24 months Duration of participation for a patient: 90 days

Detailed Description

Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in the ICU, accounting for 25% of infections in intensive care units (Réseau RAISIN 2012). From 1975 to 2003, the incidence of hospital-acquired pneumonia caused by Pseudomonas aeruginosa (PA) has almost doubled, from 9.6% to 18.1%. In a US national large-scale survey, PA was the most frequently isolated gram-negative aerobic bacterium from ICUs (23%) and also the most frequent bacterium isolated from the respiratory tract (31.6%).

PA-VAP is associated with a high mortality ranging from 40% up to 69%, and with high rates of recurrence despite adequate antimicrobial therapy. In a large randomized trial regarding the optimal duration of antibiotic therapy in overall VAPs, the rate of recurrence among the subgroup of non-fermenting Gram negative bacilli (NF-GNB) documented VAP varied between 19.0% and 32.8%, according to the randomization arm. Finally, a recently published cohort about 393 PA-VAP in 314 patients, the composite criteria failure treatment (death and recurrence) occured in 112 cases (28.5%).

Hypothesis A short duration antibiotherapy (8 days) vs. long duration antibiotherapy (15 days) in treatment of Pseudomonas aeruginosa Ventilator-Associated Pneumonia (PA-VAP) is safe and not associated with an increased mortality or recurrence rate of PA-VAP.

The demonstration of this hypothesis could lead to decrease antibiotic exposure during the hospitalization in the Intensive Care Unit (ICU) and in turn reduce the acquisition and the spread of multidrug-resistant pathogens (MDR).

Objectives

  1. Primary objective To assess the non-inferiority of a short duration of antibiotics (8 days) vs. prolonged antibiotic therapy (15 days) in Pseudomonas aeruginosa ventilator-associated pneumonia (PA-VAP) on morbi-mortality at 90 days.
  2. Secondary objectives

To compare between short and long duration of antibiotics on:

  • mortality in the ICU
  • morbidity in the ICU (mechanical ventilation, duration of hospitalization)
  • exposure and acquisition of MDR during hospitalization
  • number and types of extrapulmonary infections

Plan for the research

  1. Concise description of the primary and secondary assessment criteria

    - Primary assessment criterion: A composite endpoint combining Day-90 mortality and PA-VAP recurrence rate during hospitalization in the ICU (within 90 days).

    Recurrence will be defined a posteriori by 3 independent experts with predefined criteria: clinical suspicion of VAP (≥ two criteria including: fever> 38.5 ° C, leukocytosis > 109/L or leukopenia < 4.108/L, purulent tracheobronchial secretions and a new or persistent infiltrate on chest radiography) associated with a positive quantitative culture of a respiratory sample (bronchoalveolar lavage fluid (significant threshold ≥104 colony-forming units/mL) or plugged telescopic catheter (significant threshold ≥103 colony-forming units/mL) or quantitative endotracheal aspirate distal pulmonary secretion samples (significant threshold ≥106 colony-forming units/mL)).

    • Secondary assessment criteria:

      1. D30 and D90 mortality rate (%)
      2. Morbidity by:

        Duration of mechanical ventilation (days) Duration of hospitalization in ICU (days)

      3. Exposure to antibiotics during the hospitalization in the ICU (days)
      4. Number and types of extrapulmonary infections during the hospitalization in the ICU (n)
      5. Acquisition of MDR during the hospitalization in the ICU (swab sample of rectum and anterior nares)
  2. Description of research methodology

Randomized, open-labeled non inferiority trial comparing to parallel groups:

  • 8 days of antibiotic therapy
  • 15 days of antibiotic therapy

Antibiotic therapy Antibiotic treatment should be started just after realization of bacteriological sampling, without waiting for the result. The choice of initial antibiotic therapy will be left to the discretion of the physician but will be essentially based on the clinical context, previously antibiotic therapy, the presence or absence of risk factors for MDR (antibiotics or hospitalization in previous 90 days, current hospitalization ≥ 5 days, MV ≥ 5 days, supported in a dialysis center or residency in a nursing home), local epidemiological data, and finally if the patient is already known as being colonized by a MDR. Investigators would be strongly encouraged to convert this initial regimen into a narrow- spectrum therapy, based on culture results.

All antibiotics would be withdrawn, either at the end of day 8 or day 15, according to the randomization assignment, except those prescribed for a documented pulmonary infection recurrence before that day.

An algorithm for the initial prescription of antibiotics will be established in each ICU, the algorithm will be adapted whenever necessary to changes in the local ecology.

Number of centres participating 32 french Intensive Care Units (ICUs)

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Ventilator-Associated Pneumonia
Intervention  ICMJE
  • Drug: 8 days of effective antibiotic treatment

    Antibiotics used for usual care in PA-VAP treatment : Penicillins, Cephalosporins, Monobactams, Carbapenems, Fluoroquinolones, Aminoglycosides (list not exhaustive).

    Antibiotic treatment should be started just after realization of bacteriological sampling, and then converted into a narrow-spectrum therapy, based on culture results, for a total duration of effective antibiotic therapy against pseudomona aeruginosa of 8 days.

  • Drug: 15 days of effective antibiotic treatment

    Antibiotics used for usual care in PA-VAP treatment : Penicillins, Cephalosporins, Monobactams, Carbapenems, Fluoroquinolones, Aminoglycosides (list not exhaustive).

    Antibiotic treatment should be started just after realization of bacteriological sampling, and then converted into a narrow-spectrum therapy, based on culture results, for a total duration of effective antibiotic therapy against pseudomona aeruginosa of 15 days.

Study Arms  ICMJE
  • Experimental: 8 days of effective antibiotic treatment
    Antibiotic treatment should be started just after realization of bacteriological sampling, and then converted into a narrow-spectrum therapy, based on culture results, for a total duration of effective antibiotic therapy against PA of 8 days.
    Intervention: Drug: 8 days of effective antibiotic treatment
  • Sham Comparator: 15 days of effective antibiotic treatment
    Antibiotic treatment should be started just after realization of bacteriological sampling, and then converted into a narrow-spectrum therapy, based on culture results, for a total duration of effective antibiotic therapy against PA of 15 days.
    Intervention: Drug: 15 days of effective antibiotic treatment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 15, 2015)
600
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2018
Estimated Primary Completion Date September 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients older than 18 years
  • Mechanical ventilation ≥ 48 hours
  • Documented Pseudomonas aeruginosa ventilator-associated pneumonia:

    • Clinical suspicion (≥ two criteria including: fever> 38.5°C, leukocytosis > 109/L or leukopenia < 4.108/L, purulent tracheobronchial secretions and a new or persistent infiltrate on chest radiography).
    • Documented Pseudomonas aeruginosa positive quantitative culture of a respiratory sample: bronchoalveolar lavage fluid (significant threshold, >104cfu/ml) or plugged telescopic catheter (significant threshold, >103cfu/ml) or quantitative endotracheal aspirate (significant threshold, >106cfu/ml).
  • Written informed consent
  • Patient affiliated to French social security

Exclusion Criteria:

  • Immunocompromised patients (HIV, immunosuppressive therapy, corticosteroids> 0.5 mg / kg per day for more than a month)
  • Patients receiving antibiotic therapy for extrapulmonary infection
  • Patients in whom a procedure of withdrawing life-sustaining treatment has been established
  • Pregnancy
  • Patients included in another interventional study
  • Chronic pulmonary colonization with Pseudomonas aeruginosa: patients with Chronic Obstructive Pulmonary Disease (COPD) or bronchiectasis, with a positive respiratory sample at infra threshold rate for Pseudomonas aeruginosa (ie<103 CFUs/mL for protected specimen brush or <106 CFUs/mL for tracheal aspirate), obtained in the absence of pneumonia or exacerbation during the 6 months before the ICU admission.
  • Patient under guardianship or curatorship
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02634411
Other Study ID Numbers  ICMJE P 140923
AOM 14515 ( Other Identifier: AOM )
IDRCB n°: 2015-A00375-44 ( Other Identifier: IDRCP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Adrien Bouglé, MD APHP
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP