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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

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).

Condition or disease Intervention/treatment Phase
Pneumonia Urinary Tract Infections Bloodstream Infection Device: betaLACTA® rapid diagnostic test Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 646 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: BetaLACTA® Test-guided Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections Diagnosed in Intensive Care Unit - BLUE¬-CarbA Study
Actual Study Start Date : October 20, 2017
Estimated Primary Completion Date : November 20, 2019
Estimated Study Completion Date : January 20, 2020

Arm Intervention/treatment
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.
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

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



Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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

  2. 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).

  3. 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).

  4. 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.


  5. 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.

  6. 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.

  7. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03147807


Contacts
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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

Locations
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France
Anesthesiology and Critical Care Medicine Department Recruiting
Paris, France, 75020
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   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Marc GARNIER, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03147807     History of Changes
Other Study ID Numbers: P 150940
N° IDRCB 2016-A00941-50 ( Other Identifier: AOM 15470 )
First Posted: May 10, 2017    Key Record Dates
Last Update Posted: February 27, 2018
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Carbapenems de-escalation, rapid diagnostic test,
Carbapenem-antimicrobial de-escalation-rapid diagnostic test

Additional relevant MeSH terms:
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Infection
Communicable Diseases
Urinary Tract Infections
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Urologic Diseases