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BetaLACTA® Test for Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections in ICU (BLUE-CarbA)

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ClinicalTrials.gov Identifier: NCT03147807
Recruitment Status : Recruiting
First Posted : May 10, 2017
Last Update Posted : February 27, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE February 2, 2017
First Posted Date  ICMJE May 10, 2017
Last Update Posted Date February 27, 2018
Actual Study Start Date  ICMJE October 20, 2017
Estimated Primary Completion Date November 20, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 9, 2017)
mortality at D90 and infection recurrence during the ICU stay [ Time Frame: Day 90 ]
Composite endpoint combining 90-day mortality and percentage of infection recurrence (same GNB on the same site of infection) during the ICU stay (within the limit of 90 days). Recurrence will be defined a posteriori by 3 independent experts, blinded of the allocation group of patients in whom a suspected recurrence would have occurred, with predefined criteria.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03147807 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 9, 2017)
  • Exposure to carbapenems [ Time Frame: from Day 0, through ICU discharge or until 28 days after inclusion in case of prolonged ICU stay ]
    • Number of days with carbapenem treatment after inclusion during ICU stay (within the limit of 28 days)
    • Number of carbapenems Defined Daily Doses (DDD) after inclusion during ICU stay (within the limit of 28 days)
    • Number of carbapenem-free and antibiotic free days at day 28 after inclusion
  • Total use of ICU and hospital resources and cost-effectiveness of early de-escalation compared to standard de-escalation. [ Time Frame: from Day 0,throught hospital discharge or until 28 days after inclusion in case of prolonged ICU stay ]
    • ICU and hospital lengths of stay following randomization;
    • Total cost and incremental cost-effectiveness ratio (cost per additional death/ infection averted).
  • Occurrence of other infections. [ Time Frame: From Day 0 to ICU discharge (within the limit of 90 days). ]
    Percentage of new infections (same site of infection with other bacteria or other site of infection) during ICU stay (within the limit of 90 days).
  • Colonization of the digestive tractus of patients with 3rd generation cephalosporins (3rdGC) resistant Gram-negative bacteria [ Time Frame: From Day 0, through ICU discharge or until 28 days after inclusion in case of prolonged ICU stay ]
    New colonization of patients' digestive tractus with 3rdGC-resistant GNB (i.e. ESBL-producing Enterobacteriaceae, Carbapenemase-producing Enterobacteriaceae, high-concentration AmpC cephalosporinase-producing Enterobacteriaceae, multi-resistant non-fermenting GNB, etc.) will be assessed comparing the results of the culture on selective media of rectal swabs performed at inclusion and at D3, at the end of the antibiotic treatment, and at ICU discharge. Characterization of acquired 3rdGC-resistant GNB and determination of their resistance mechanism(s) will be performed using standard microbiological processes and molecular biology.
  • Composition of intestinal microbiota at Day 0 [ Time Frame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days ]
    To compare the composition of intestinal microbiota among patients with an early de-escalation guided by the betaLACTA® test results and a standard de-escalation on antibiogram results at 48-72h.
  • Composition of intestinal microbiota at day 3 [ Time Frame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days ]
    To compare the evolution of intestinal microbiota of patients after exposure to different betalactam antibiotics, from carbapenems or cefepim/ceftazidim during the empirical treatment, to the definitive beta-lactam antibiotic chosen to cure the infection after antibiotic susceptibility test results.
  • Composition of intestinal microbiota after antibiotic exposur [ Time Frame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days ]
    To compare the outcomes of ICU patients (mortality at Day 90, occurrence of infection, ICU length of stay, etc.) according to the composition of their intestinal microbiota and to its evolution during antibiotic treatment.
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 BetaLACTA® Test for Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections in ICU
Official Title  ICMJE BetaLACTA® Test-guided Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections Diagnosed in Intensive Care Unit - BLUE¬-CarbA Study
Brief Summary

The emergence and rapid worldwide spread of Extended- Spectrum Beta-Lactamase-producing enterobacteriaceae (ESBLE) both in hospital and community, led physicians, and notably intensivists, to prescribe more carbapenems, particularly in the most fragile patients such as ICU patients. Unfortunately, the increased carbapenem consumption favored the emergence of carbapenem resistance mechanisms. Moreover, several preliminary results suggest that carbapenem could markedly impact the human intestinal microbiota, Thus, reduction of carbapenem exposure is widely desired both by national and international antibiotic plans. Therefore, the use of rapid diagnostic tests evaluating bacterial resistance to reduce inappropriate exposure to carbapenems could be a relevant solution. Due to its good diagnostic performance, the betaLACTA® test could meet these objectives.

Experimental plan :

Randomized, open-labeled non-inferiority clinical trial involving an in vitro diagnostic medical device (close to a phase III study), comparing two parallel groups:

  • Experimental group: early carbapenems de-escalation since the second dose, guided by results of the betaLACTA® test performed directly on the bacterial pellet from the microbiological sample positive on direct examination.
  • Control group: carbapenems de-escalation guided by definitive results of the antibiotic susceptibility test obtained 48 to 72h after microbiological sampling (reference strategy).
Detailed Description

This study is conducted on ICU patients with a suspected pneumonia, primary blood-stream infection (BSI), and/or urinary tract infection (UTI).

The primary objective of the study is to demonstrate that in ICU infections treated empirically by carbapenems and documented with GNB on direct examination of a respiratory, urinary and/or blood sample(s), the early de-escalation guided by the results of the betaLACTA® test is not inferior to the reference strategy de-escalating on antibiotic susceptibility test (AST) results obtained 48-72h after sampling, in terms of mortality at D90 and infection recurrence in ICU.

The secondary objectives are to compare the early de-escalation guided by the betaLACTA® test results to the reference strategy de-escalating on the AST results on:

  • The exposure to carbapenems.
  • The total use of ICU and hospital resources and the cost-effectiveness.
  • The occurrence of other infections.
  • The colonization of the digestive tractus of patients with 3rd generation cephalosporins (3rdGC) resistant Gram-negative bacteria (GNB).

In addition, an ancillary study will be performed (only in participating centers from the Ile de France region) to compare :

  • The composition of the intestinal microbiota among patients with an early de-escalation guided by the betaLACTA® test results and a standard de-escalation on AST results at 48-72h.
  • The evolution of intestinal microbiota of patients after exposure to different beta-lactam antibiotics, from carbapenems or cefepim/ceftazidim during the empirical treatment, to the definitive beta-lactam antibiotic chosen to cure the infection after antibiotic susceptibility test results.
  • The outcomes of ICU patients (mortality at D90, occurrence of infection, ICU length of stay, etc.) according to the composition of their intestinal microbiota and to its evolution during antibiotic treatment.

To meet these objectives, 646 patients will be enrolled.

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
  • Pneumonia
  • Urinary Tract Infections
  • Bloodstream Infection
Intervention  ICMJE Device: betaLACTA® rapid diagnostic test
Since ≥1 bacteriological sample(s) from ICU patients empirically treated with carbapenems (i.e. respiratory sample such as quantitative tracheobronchial aspirate with available volume ≥1 mL; urinary sample such as single catheter urine specimen; or blood culture) is positive for ≥2 GNB/field on direct examination, empirical carbapenem will be adapted: 1) early, since the second dose, according to the results of the betaLACTA® rapid diagnostic test (BLT) in the intervention arm (i.e. de-escalation to cefepim or to ceftazidim+amikacin in case of negativity, and carbapenem continuation in case of positivity); or 2) after 48-72h according to the results of the antibiotic susceptibility test in the control arm.
Other Name: betaLACTA® test
Study Arms  ICMJE
  • Experimental: betaLACTA® result given to physician
    In the experimental group, betaLACTA® rapid diagnostic test guided de-escalation result will be given to physician at Day 0 and empirical carbapenems will be de-escalated to Cefepime or Ceftazidime +/- Amikacin since the second dose.
    Intervention: Device: betaLACTA® rapid diagnostic test
  • No Intervention: betaLACTA® result NOT given to physician
    In the control group, betaLACTA® result will not be given to physician and patients will receive empirical carbapenem during the time required to obtain final results of antibiotic susceptibility test
Publications * Garnier M, Gallah S, Vimont S, Benzerara Y, Labbe V, Constant AL, Siami S, Guerot E, Compain F, Mainardi JL, Montil M, Quesnel C; BLUE-CarbA study group. Multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic βLACTA test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the BLUE-CarbA protocol. BMJ Open. 2019 Feb 19;9(2):e024561. doi: 10.1136/bmjopen-2018-024561.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 9, 2017)
646
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 20, 2020
Estimated Primary Completion Date November 20, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • ICU patients ≥18 years.
  • With a suspected pneumonia (according to CPIS definition), primary blood-stream infection (according to CDC definition), and/or urinary tract infection (according to IDSA Guidelines).
  • And presence of ≥2 GNB/field on direct examination of a respiratory sample (quantitative bronchial aspirate with an available volume ≥ 1mL), urinary sample or blood culture.
  • Leading to an empirical carbapenem prescription, not administered for more than 6 hours when considering the inclusion of the patient.
  • Written informed consent signed by the patient / the trustworthy person / the next-of-kin / close relative, or inclusion in case of emergency and written informed consent will been signed by the patient as soon as possible.
  • Patients affiliated to French social security.

Exclusion Criteria:

  • Pregnancy.
  • Allergy to beta-lactams.
  • Patients already treated with ongoing carbapenems for another documented infection, blocking carbapenem de-escalation.
  • Patients included in another interventional study.
  • Patients in whom a procedure of withdrawing life-sustaining treatment was decided before inclusion.
  • Moribund patients.
  • Patients with aplasia.
  • Patients under tutorship/curatorship or patient deprived of freedom
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: Marc GARNIER, MD, PhD +33(1) 56 01 6 3 84 marc.garnier@aphp.fr
Contact: Christophe QUESNEL, MD, PhD +33(1) 56 01 65 71 christophe.quesnel@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03147807
Other Study ID Numbers  ICMJE P 150940
N° IDRCB 2016-A00941-50 ( Other Identifier: AOM 15470 )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marc GARNIER, MD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date May 2017

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