A Platform Trial for Gram Negative Bloodstream Infections
NCT ID: NCT06537609
Last Updated: 2025-09-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
NA
2500 participants
INTERVENTIONAL
2024-04-24
2028-04-30
Brief Summary
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The initial vanguard pilot RCT (NCT05893147) started on 29 August 2023 and has successfully completed the pilot phase on 24-Apr-2024. All patients enrolled in the vanguard phase are part of the main platform trial.
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Detailed Description
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BALANCE+ addresses the significant health concern of BSIs, which have high morbidity and mortality rates, exacerbated by the global public health threat of antimicrobial resistance (AMR). With rising resistance rates and limited new drug development, effective treatment strategies for BSIs remain under-researched.
BALANCE+ follows the BALANCE trial, which evaluated duration of antibiotic treatment, and aims to further investigate critical questions in managing Gram-negative BSIs. This platform trial will explore various aspects of BSI treatment, including antibiotic de-escalation, oral antibiotic choices, central line management, treatment of specific pathogens, and the necessity of follow-up blood cultures.
BALANCE+ is using Bayesian methods without a fixed sample size. Interim analyses will occur after every 1000th patient in each domain, and then for every 200th patient thereafter. The trial will stop if futility or superiority thresholds are met, or if a domain reaches its ceiling sample size (2500 patients for most domains and 4000 for the beta-lactam versus non-beta-lactam domain) without meeting a stopping threshold.
A vanguard pilot trial involving over 150 patients at 9 hospitals across Canada confirmed the feasibility of the BALANCE+ trial. The main trial will include patients from the vanguard pilot phase since there has been no major change in the overall study design and domains. The adaptive design allows for interim analyses and adjustments by adding or removing domains as per the statistical analysis plan, enhancing the trial's efficiency and relevance.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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De-escalation VS No De-escalation
De-escalation VS No De-escalation
No de-escalation group: continue to receive the same antibiotic that was started initially (as long as it is confirmed to be effective based on the blood culture sensitivity result). De-escalation is only allowed within 7 days if patient is being discharged from hospital.
De-escalation group: switched to narrower spectrum antibiotic (based on spectrum scale specified in protocol).
Oral beta-lactams VS Oral Non-beta-lactams
Oral beta-lactams VS non beta-lactams
Beta-lactam antibiotic: This can be, but not limited to, amoxicillin, amoxicillin-clavulanate, cephalexin, cefadroxil, or cefixime.
Non beta-lactam antibiotic: This can be ciprofloxacin, moxifloxacin, levofloxacin or trimethoprim-sulfamethoxazole.
Central vascular catheter retention VS Central vascular catheter replacement
Central vascular catheter retention VS Central vascular catheter replacement
Central vascular catheter replacement: the catheter will be changed by the treating team as soon as possible and within a maximum of 72 hours from blood culture finalization
Central vascular catheter retention: the catheter will not be changed and will be retained until it is non functional or no longer needed.
Cephalosporin VS Carbapenem for low risk AmpC organisms
Cephalosporin VS Carbapenem for low risk AmpC organisms
Cephalosporin (ceftriaxone) at standard doses
Carbapenem (Meropenem or Ertapenem) at standard doses
Routine follow-up blood culture VS No routine follow-up blood culture
Routine follow-up blood culture VS No routine follow-up blood culture
Routine follow-up blood culture: routine repeat blood collection 4 days from the index blood collection with positive bacteria.
No follow-up blood culture: no routine repeat blood collection 4 days from the index blood collection with positive bacteria
Interventions
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De-escalation VS No De-escalation
No de-escalation group: continue to receive the same antibiotic that was started initially (as long as it is confirmed to be effective based on the blood culture sensitivity result). De-escalation is only allowed within 7 days if patient is being discharged from hospital.
De-escalation group: switched to narrower spectrum antibiotic (based on spectrum scale specified in protocol).
Oral beta-lactams VS non beta-lactams
Beta-lactam antibiotic: This can be, but not limited to, amoxicillin, amoxicillin-clavulanate, cephalexin, cefadroxil, or cefixime.
Non beta-lactam antibiotic: This can be ciprofloxacin, moxifloxacin, levofloxacin or trimethoprim-sulfamethoxazole.
Central vascular catheter retention VS Central vascular catheter replacement
Central vascular catheter replacement: the catheter will be changed by the treating team as soon as possible and within a maximum of 72 hours from blood culture finalization
Central vascular catheter retention: the catheter will not be changed and will be retained until it is non functional or no longer needed.
Cephalosporin VS Carbapenem for low risk AmpC organisms
Cephalosporin (ceftriaxone) at standard doses
Carbapenem (Meropenem or Ertapenem) at standard doses
Routine follow-up blood culture VS No routine follow-up blood culture
Routine follow-up blood culture: routine repeat blood collection 4 days from the index blood collection with positive bacteria.
No follow-up blood culture: no routine repeat blood collection 4 days from the index blood collection with positive bacteria
Eligibility Criteria
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Inclusion Criteria
* positive blood culture with Gram negative (GN) bacterium
\- included in BALANCE+ platform
* included in BALANCE+ platform
* initially treated with intravenous antibiotics, but clinical team transitioning patient to oral/enteral antibiotic within 7 days of starting treatment
* included in BALANCE+ platform
* has an indwelling central vascular catheter that was already in place within the 48-hour period before the onset of bloodstream infection (i.e. is not a new catheter placed within 48 hours of the onset of infection)
* included in BALANCE+ platform
* positive blood culture with GN bacterium, of the following species: i. Serratia spp. ii Morganella spp. iii Providencia spp. iv Proteus spp. other than P.mirabilis
* organism is susceptible to ceftriaxone
\- included in BALANCE+ platform
Exclusion Criteria
* moribund patient, not expected to survive \> 72 hours
* previously enrolled in the platform trial
* not eligible for any domain at the time of screening
1. De-escalation versus no de-escalation domain
* receiving an empiric antibiotic regimen at the time of blood culture finalization to which the GN pathogen(s) are not sensitive
* arbapenem-non-susceptible
* no de-escalation option due to any or all of:
* antimicrobial resistance
* allergies
* medical contraindications
* drug-drug interaction risk
* other relevant reason
* patients with a suspected or proven polymicrobial source of infection
* \> 24 hours since index blood culture susceptibility results finalization
2. Beta-lactam versus non-beta-lactam oral/enteral treatment domain
* enrolled in an arm of another BALANCE+ platform domain which limits the use of oral/enteral therapy:
* no-de-escalation arm (patients in the no de-escalation arm cannot be randomized into this domain unless they are ready for discharge home, in which case de-escalation is allowable to oral agents at discharge)
* no non-beta-lactam options due to any or all of:
* resistance
* allergies
* medical contraindications
* drug-interaction risk
* other relevant reason
* no beta-lactam options due to any or all of:
* resistance
* allergies
* medical contraindications
* drug-interaction risk
* other relevant reason
* pregnancy
* already received \>24 hours of oral antibiotics after index blood culture finalization
3. Central vascular catheter replacement domain
* patient has no ongoing need for a central vascular catheter
* patient has definite indication for central vascular catheter removal
* ongoing septic shock with definite/probable line source
* concomitant S. aureus bacteremia
* concomitant candidemia
* local suppurative signs (severe redness, warmth, pain, swelling or fluctuance/collection) necessitating catheter removal, or other clinical evidence of infected line (e.g. imaging/echocardiographic findings)
4. Low-risk AmpC domain
* severe allergy to beta-lactams (e.g., type 4 hypersensitivity reaction or DRESS)
* baseline phenotypic non-susceptiblity to ceftriaxone
* more than 1 calendar day beyond availability of susceptibility results
5. Follow up blood culture domain
* patient died or discharged from hospital prior to day 4
* blood culture already collected by the treating team at day 4±1
* \>5 days since index positive blood culture collection
* definite indication for repeat blood culture testing
* concomitant S. aureus bacteremia
* concomitant Candidemia
* clinical suspicion for infective endocarditis
0 Years
130 Years
ALL
No
Sponsors
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Canadian Institutes of Health Research (CIHR)
OTHER_GOV
Sunnybrook Health Sciences Centre
OTHER
Responsible Party
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Dr. Nick Daneman
Clinician Scientist
Principal Investigators
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Nick Daneman, MD
Role: PRINCIPAL_INVESTIGATOR
Sunnybrook Health Sciences Centre
Rob Fowler, MD
Role: PRINCIPAL_INVESTIGATOR
Sunnybrook Health Sciences Centre
Locations
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St George Hospital
Kogarah, New South Wales, Australia
John Hunter Hospital
New Lambton, New South Wales, Australia
Redcliffe Hospital
Redcliffe, Queensland, Australia
Sunshine Coast University Hospital
Sunshine Coast, Queensland, Australia
Monash Medical Center
Clayton, Victoria, Australia
Fiona Stanley Hospital
Murdoch, Western Australia, Australia
St John of God
Murdoch, Western Australia, Australia
Foothills Hospital
Calgary, Alberta, Canada
Peter Lougheed Centre
Calgary, Alberta, Canada
Rockyview General Hospital
Calgary, Alberta, Canada
South Health Campus
Calgary, Alberta, Canada
University of Alberta
Edmonton, Alberta, Canada
Surrey Memorial Hospital
Surrey, British Columbia, Canada
Vancouver General Hospital
Vancouver, British Columbia, Canada
Grace Hospital
Winnipeg, Manitoba, Canada
Health Sciences Centre
Winnipeg, Manitoba, Canada
St. Boniface Hospital
Winnipeg, Manitoba, Canada
Dr. Everett Chalmers Regional Hospital
Fredericton, New Brunswick, Canada
Eastern Regional Health Authority
St. John's, Newfoundland and Labrador, Canada
Trillium Health Partners - Mississauga Hospital
Mississauga, Ontario, Canada
Humber River Health system
North York, Ontario, Canada
North York General Hospital
North York, Ontario, Canada
The Ottawa Hospital
Ottawa, Ontario, Canada
Niagara Health System
St. Catharines, Ontario, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
Michael Garron Hospital
Toronto, Ontario, Canada
Mount Sinai Hospital
Toronto, Ontario, Canada
St. Joseph's Health Centre
Toronto, Ontario, Canada
University Health Network
Toronto, Ontario, Canada
CHU de Québec - Université Laval
Laval, Quebec, Canada
Hôpital de la Cité de la Santé
Laval, Quebec, Canada
Montreal General Hospital- McGill
Montreal, Quebec, Canada
Royal Victoria Hospital- McGill
Montreal, Quebec, Canada
Université de Sherbrooke
Sherbrooke, Quebec, Canada
Universidad de La Sabana
Chía, Cundinamarca, Colombia
Sheba Medical Center
Ramat Gan, Tel Aviv, Israel
Countries
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Central Contacts
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Facility Contacts
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Judeil Krian Teus
Role: backup
Role: backup
Ranjani Somayaji, MD
Role: primary
Peter Daley, MD
Role: primary
Mobina Khurram
Role: backup
Derek McFadden, MD
Role: primary
Aidan Findlater, MD
Role: primary
Christopher Kandel, MD
Role: primary
Michael Fralick, PhD
Role: primary
Bryan Coburn, MD
Role: primary
François Lamontagne, MD
Role: primary
Other Identifiers
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4369-1
Identifier Type: -
Identifier Source: org_study_id
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