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

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ClinicalTrials.gov Identifier: NCT04291768
Recruitment Status : Recruiting
First Posted : March 2, 2020
Last Update Posted : November 19, 2020
Sponsor:
Information provided by (Responsible Party):
Thomas Benfield, Hvidovre University Hospital

Brief Summary:

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%.


Condition or disease Intervention/treatment Phase
Gram-negative Bacteremia Urinary Tract Infection Bacterial Other: Shortened antibiotic treatment Other: Standard antibiotic treatment Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Short Course Antibiotic Treatment of Gram-negative Bacteremia: A Multicenter, Randomized, Non-blinded, Non-inferiority Interventional Study
Actual Study Start Date : March 11, 2020
Estimated Primary Completion Date : October 1, 2023
Estimated Study Completion Date : October 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

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.




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. Mortality [ Time Frame: 14, 30 and 90 days ]
    Number of deaths by any cause

  2. 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

  3. Type of antibiotic treatment [ Time Frame: 90 days ]
    Antibiotic treatment for Gram-negative bacteremia given by antibiogram

  4. Duration of antibiotic treatment [ Time Frame: 90 days ]
    Duration of antibiotic treatment for Gram-negative bacteremia given by antibiogram

  5. 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

  6. Hospital re-admission [ Time Frame: 30 and 90 days ]
    Number of participants with readmissions for reasons related to or unrelated to Gram-negative bacteremia

  7. Antibiotic adverse events [ Time Frame: 90 days ]
    Number of participants with adverse events with possible relation to the antibiotic treatment of Gram-negative bacteremia

  8. Use of antimicrobials after discharge [ Time Frame: 90 days ]
    Days of antibiotic treatment for any reason after hospital discharge

  9. 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

  10. 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.

  11. Clostridioides difficile infection [ Time Frame: 90 days ]
    Number of participants with Clostridioides difficile infection

  12. 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.



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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:

  • 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 (>1 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

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): NCT04291768


Contacts
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Contact: Sandra Tingsgård, MD +4520544094 sandra.tingsgaard@regionh.dk
Contact: Thomas Benfield, MD DMSc thomas.lars.benfield@regionh.dk

Locations
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Denmark
University Hospital of Aalborg Not yet recruiting
Aalborg, Denmark, 9000
Contact: Henrik Nielsen, MD DMSc       henrik.nielsen@rn.dk   
Rigshospitalet Not yet recruiting
Copenhagen, Denmark, 2100
Contact: Jan Gertoft, MD DMSc       jan.gerstoft@regionh.dk   
Gentofte Hospital Recruiting
Hellerup, Denmark, 2900
Contact: Pernille Ravn, MD PhD       pernille.ravn.02@regionh.dk   
Herlev Hospital Recruiting
Herlev, Denmark, 2730
Contact: Suzanne Lunding, MD PhD       suzanne.lunding.01@regionh.dk   
Herning Hospital Not yet recruiting
Herning, Denmark, 7400
Contact: Rajesh Mohey, MD PhD         
Contact       rajemohe@rm.dk   
Nordsjaellands Hospital Recruiting
Hillerød, Denmark, 3400
Contact: Birgitte Lindegaard Madsen, MD PhD       birgitte.lindegaard.madsen@regionh.dk   
Hvidovre Hospital Recruiting
Hvidovre, Denmark, 2650
Contact: Sandra Tingsgård, MD    +4520544094    sandra.tingsgaard@regionh.dk   
Kolding Hospital Not yet recruiting
Kolding, Denmark, 6000
Contact: Janne Jensen, MD       janne.jensen@rsyd.dk   
Odense University Hospital Not yet recruiting
Odense, Denmark, 5000
Contact: Isik Johansen, MD DMSc       isik.somuncu.johansen@rsyd.dk   
Roskilde Hospital Not yet recruiting
Roskilde, Denmark, 4000
Contact: Lothar Wiese, MD PhD       low@regionsjaelland.dk   
Regionshospitalet Silkeborg Not yet recruiting
Silkeborg, Denmark, 8600
Contact: Britta Tarp, MD PhD       brittarp@rm.dk   
University Hospital of Aarhus Not yet recruiting
Århus, Denmark, 8200
Contact: Lars Østergaard, MD DMSc       larsoest@rm.dk   
Sponsors and Collaborators
Thomas Benfield
Investigators
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Principal Investigator: Sandra Tingsgård, MD Hvidovre University Hospital
  Study Documents (Full-Text)

Documents provided by Thomas Benfield, Hvidovre University Hospital:
Statistical Analysis Plan  [PDF] February 6, 2020

Publications:

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Responsible Party: Thomas Benfield, Clinical Professor, Hvidovre University Hospital
ClinicalTrials.gov Identifier: NCT04291768    
Other Study ID Numbers: 190801
2019-003282-17 ( EudraCT Number )
H-19085920 ( Other Identifier: National Ethics Comittee of Denmark )
First Posted: March 2, 2020    Key Record Dates
Last Update Posted: November 19, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Thomas Benfield, Hvidovre University Hospital:
Gram-negative bacteremia
Urinary tract infection
Shortened antibiotic treatment
Bacterial infection
Additional relevant MeSH terms:
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Infection
Urinary Tract Infections
Bacteremia
Bacterial Infections
Urologic Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents