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

Sponsor

Thomas Benfield (Other)

Overall Status

Recruiting

CT.gov ID

NCT04291768

Collaborator

(none)

380

Enrollment

Locations

Arms

42.7

Anticipated Duration (Months)

31.7

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

Anticipated 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 :

Mar 11, 2020

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2023

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

90-day survival without clinical or microbiological failure to treatment [90 days]
90-day survival without clinical or microbiological failure to treatment as defined: All-cause mortality from day of randomization and until day 90 Microbiological failure: Recurrent bacteremia due to the same microorganism as verified by sequence analysis occurring from day of randomization and until day 90 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 Distant complications of initial infection, defined by growth of the same bacteria as in the initial bacteremia (e.g. endocarditis, meningitis) Local suppurative complication that was not present at infection onset (e.g. renal abscess in pyelonephritis)

Secondary Outcome Measures

Mortality [14, 30 and 90 days]
Number of deaths by any cause
Total duration of antibiotic treatment [90 days]
Days that the participant receives antibiotic treatment for Gram-negative bacteremia, adding intravenous and oral therapy
Type of antibiotic treatment [90 days]
Antibiotic treatment for Gram-negative bacteremia given by antibiogram
Duration of antibiotic treatment [90 days]
Duration of antibiotic treatment for Gram-negative bacteremia given by antibiogram
Total length of hospital stay [90 days]
Days from the date of hospital admission for Gram-negative bacteremia to the date of discharge
Hospital re-admission [30 and 90 days]
Number of participants with readmissions for reasons related to or unrelated to Gram-negative bacteremia
Antibiotic adverse events [90 days]
Number of participants with adverse events with possible relation to the antibiotic treatment of Gram-negative bacteremia
Use of antimicrobials after discharge [90 days]
Days of antibiotic treatment for any reason after hospital discharge
Severe adverse events [90 days]
Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines
Acute kidney injury [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.
Clostridioides difficile infection [90 days]
Number of participants with Clostridioides difficile infection
Multidrug-resistance organism [90 days]
Multidrug-resistance organism defined as identification of resistant bacteria in a clinical specimen obtained only from a clinical infection.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Hospital of Aalborg	Aalborg	Denmark	9000
2	Rigshospitalet	Copenhagen	Denmark	2100
3	Gentofte Hospital	Hellerup	Denmark	2900
4	Herlev Hospital	Herlev	Denmark	2730
5	Herning Hospital	Herning	Denmark	7400
6	Nordsjaellands Hospital	Hillerød	Denmark	3400
7	Hvidovre Hospital	Hvidovre	Denmark	2650
8	Kolding Hospital	Kolding	Denmark	6000
9	Odense University Hospital	Odense	Denmark	5000
10	Roskilde Hospital	Roskilde	Denmark	4000
11	Regionshospitalet Silkeborg	Silkeborg	Denmark	8600
12	University Hospital of Aarhus	Århus	Denmark	8200