Shortened Antibiotic Treatment of 5 Days in Gram-negative Bacteremia (GNB5)

February 6, 2023 updated by: Thomas Benfield

Short Course Antibiotic Treatment of Gram-negative Bacteremia: A Multicenter, Randomized, Non-blinded, Non-inferiority Interventional Study

GNB5 is an investigator-initiated multicentre non-inferiority randomized controlled trial which aims to assess the efficacy and safety of shortened antibiotic for patients hospitalized with a Gram negative bacteremia with a urinary tract source of infection (GNB).

Five days after initiation of antimicrobial therapy for GNB, participants are randomized 1:1 to parallel treatment arms: 5 days (intervention) or minimum 7 days (control) of antibiotic treatment. The intervention group discontinues antibiotics at day 5 if clinically stable and afebrile. The control group receives antibiotics for a duration of 7 days or longer at the discretion of the treating physician.

The primary outcome is 90-day survival without clinical or microbiological failure to treatment, which will be tested with a non inferiority margin of 10%.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Introduction: Prolonged use of antibiotics is closely related to antibiotic-associated infections, anti-microbial resistance and adverse drug events. The optimal duration of antibiotic treatment for Gram-negative bacteremia (GNB) with a urinary tract source of infection is poorly defined.

Methods and analysis: Investigator initiated multicenter, non-blinded, non-inferiority randomized controlled trial with two parallel treatment arms. One arm will receive shortened antibiotic treatment of 5 days and the other arm will receive standard antibiotic treatment of 7 days or longer. Randomization will occur in equal proportion (1:1) no later than day 5 of efficacious antibiotic treatment as determined by antibiogram. Immunosuppressed patients and those with GNB due to non-fermenting bacilli (Acinetobacter spp, Pseudomonas spp), Brucella spp, Fusobacterium spp or polymicrobial growth are ineligible.

Primary endpoint is 90-day survival without clinical or microbiological failure to treatment. Secondary endpoints include all-cause mortality, total duration of antibiotic treatment, hospital re-admission and Clostridioides difficile infection. Interim safety analysis will be performed after the recruitment of every 100 patients. Given an event rate of 12%, a margin of 10% and 90% power, the required sample size to determine non-inferiority is 380 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.

Ethics and dissemination: Approval by Ethics Committee and National Competent Authorities will be obtained before initiation of the trial. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Impact: Demonstration of non-inferiority will provide needed evidence to safely shorten antibiotic treatment duration in GNB with a urinary tract source of infection and thereby reduce the risk of adverse events and development of resistance associated with use of antibiotics

Study Type

Interventional

Enrollment (Anticipated)

380

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aalborg, Denmark, 9000
        • Not yet recruiting
        • University Hospital of Aalborg
      • Copenhagen, Denmark, 2100
        • Not yet recruiting
        • Rigshospitalet
      • Copenhagen, Denmark, 2400
        • Recruiting
        • Bispebjerg Hospital
        • Contact:
          • Jesper Andreas Knudsen, MD, PhD
      • Hellerup, Denmark, 2900
        • Recruiting
        • Gentofte Hospital
      • Herlev, Denmark, 2730
        • Recruiting
        • Herlev Hospital
      • Herning, Denmark, 7400
        • Not yet recruiting
        • Herning Hospital
      • Hillerød, Denmark, 3400
        • Recruiting
        • Nordsjaellands Hospital
      • Hvidovre, Denmark, 2650
        • Recruiting
        • Hvidovre Hospital
      • Kolding, Denmark, 6000
        • Not yet recruiting
        • Kolding Hospital
      • Odense, Denmark, 5000
        • Not yet recruiting
        • Odense University Hospital
      • Roskilde, Denmark, 4000
        • Not yet recruiting
        • Roskilde Hospital
      • Silkeborg, Denmark, 8600
        • Not yet recruiting
        • Regionshospitalet Silkeborg
      • Århus, Denmark, 8200
        • Not yet recruiting
        • University Hospital of Aarhus

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age >18 years
  • Blood culture positive for Gram-negative bacteria
  • Evidence of urinary tract source of infection (positive urine culture or at least one clinical symptom compatible with urinary tract infection)
  • Antibiotic treatment with antimicrobial activity to Gram-negative bacteria administrated within 12 hours of first blood culture
  • Temperature <37.8°C at randomization
  • Clinically stabile at randomization (systolic blood pressure > 90 mm Hg, heart rate <100 beats/min., respiratory rate <24/minute, peripheral oxygen saturation > 90 %)
  • Oral and written informed consent

Exclusion Criteria:

  • Antibiotic treatment (>2 day) with antimicrobial activity to Gram-negative bacteria within 14 days of inclusion
  • Gram-negative bacteremia within 30 days of blood culture
  • Immunosuppression (Untreated HIV-infection, Neutropenia (absolute neutrophil count < 1.0 x 109/l), Untreated terminal cancer, Receiving immunosuppressive agents (ATC-code L04A), Corticosteroid treatment (≥20 mg/day prednisone or the equivalent for >14 days) within the last 30 days, Chemotherapy within the last 30 days, Immunosuppressed after solid organ transplantation, Asplenia)
  • Polymicrobial growth in blood culture
  • Bacteremia with non-fermenting Gram-negative bacteria (Acinetobacter spp, Burkholderia spp, Pseudomonas spp), Brucella spp, or Fusobacterium spp
  • Failure to remove source of infection within 72 hours of first blood culture (e.g. change of catheter á demeure)
  • Pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Intervention group
Shortened antibiotic treatment of 5 days
Other: Shortened antibiotic treatment
Shortened antibiotic treatment of 5 days. Participation in the study will only affect treatment duration and will have no influence on the choice of treatment in respect to type and dose of antibiotic treatment.
ACTIVE_COMPARATOR: Control group
Standard antibiotic treatment of minimum 7 days at the discretion of treating physician
Other: Standard antibiotic treatment
Standard antibiotic treatment of minimum 7 days at the discretion of treating physician. Participation in the study will only affect treatment duration and will have no influence on the choice of treatment in respect to type and dose of antibiotic treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
90-day survival without clinical or microbiological failure to treatment
Time Frame: 90 days

90-day survival without clinical or microbiological failure to treatment as defined:

  1. All-cause mortality from day of randomization and until day 90
  2. Microbiological failure: Recurrent bacteremia due to the same microorganism as verified by sequence analysis occurring from day of randomization and until day 90

  3. Clinical failure: Re-initiation of therapy against Gram-negative bacteremia for more than 48 hours due to clinical worsening suspected to be due to the initial infecting organism and for which there is no alternate diagnosis/pathogen suspected from the day of randomization and until day 90

    1. Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia (e.g. endocarditis, meningitis)
    2. Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis)
90 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 14, 30 and 90 days
Number of deaths by any cause
14, 30 and 90 days
Total duration of antibiotic treatment
Time Frame: 90 days
Days that the participant receives antibiotic treatment for Gram-negative bacteremia, adding intravenous and oral therapy
90 days
Type of antibiotic treatment
Time Frame: 90 days
Antibiotic treatment for Gram-negative bacteremia given by antibiogram
90 days
Duration of antibiotic treatment
Time Frame: 90 days
Duration of antibiotic treatment for Gram-negative bacteremia given by antibiogram
90 days
Total length of hospital stay
Time Frame: 90 days
Days from the date of hospital admission for Gram-negative bacteremia to the date of discharge
90 days
Hospital re-admission
Time Frame: 30 and 90 days
Number of participants with readmissions for reasons related to or unrelated to Gram-negative bacteremia
30 and 90 days
Antibiotic adverse events
Time Frame: 90 days
Number of participants with adverse events with possible relation to the antibiotic treatment of Gram-negative bacteremia
90 days
Use of antimicrobials after discharge
Time Frame: 90 days
Days of antibiotic treatment for any reason after hospital discharge
90 days
Severe adverse events
Time Frame: 90 days
Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines
90 days
Acute kidney injury
Time Frame: 90 days
Number of participants with acute kidney injury is defined according to RIFLE criteria as increased creatinine level x 1.5 from baseline or estimated glomerular filtration rate (eGFR) decrease >25% or urine output of <0.5 ml/kg/h for 6 hours.
90 days
Clostridioides difficile infection
Time Frame: 90 days
Number of participants with Clostridioides difficile infection
90 days
Multidrug-resistance organism
Time Frame: 90 days
Multidrug-resistance organism defined as identification of resistant bacteria in a clinical specimen obtained only from a clinical infection.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Thomas Benfield

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 11, 2020

Primary Completion (ANTICIPATED)

October 1, 2026

Study Completion (ANTICIPATED)

October 1, 2026

Study Registration Dates

First Submitted

February 24, 2020

First Submitted That Met QC Criteria

February 27, 2020

First Posted (ACTUAL)

March 2, 2020

Study Record Updates

Last Update Posted (ACTUAL)

February 8, 2023

Last Update Submitted That Met QC Criteria

February 6, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 190801
  • 2019-003282-17 (EUDRACT_NUMBER)
  • H-19085920 (OTHER: National Ethics Comittee of Denmark)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Demographics, medical history, and laboratory data will be preserved to validate and replicate described research. Study protocol and statistical analysis plan will be publicly available.

Data will be collected in the electronic data capture system (REDCap) and analyzed using open-source statistical packages in R. Data will be available immediately following the publication of the primary outcome. Data will be preserved for 10 upon study start. Anonymized trial data will be made available through relevant public databases when the trial ends. On request, anonymized patient-level data, the statistical code, and other relevant supporting information will be made available by contact with the corresponding author. Study data will be published only in pseudonymous form. Compliance with the plan will be monitored by the primary investigator routinely.

IPD Sharing Time Frame

Data will be available immediately following the publication of the primary outcome. Data will be preserved for 10 upon study start.

IPD Sharing Access Criteria

On request, anonymized patient-level data, the statistical code, and other relevant supporting information will be made available by contact with the corresponding author.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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