An interventional study of De-escalation VS No De-escalation and Oral beta-lactams VS non beta-lactams in Gram-negative Bacteremia, sponsored by Sunnybrook Health Sciences Centre. Recruiting at 41 sites in 5 countries. Open to participants aged 0 Years to 130 Years. Per ClinicalTrials.gov, last updated 2026-11-09.
Sponsored by Sunnybrook Health Sciences Centre · Not applicable, Interventional, and Treatment
BALANCE+ is a perpetual multiple domain randomized controlled platform trial to evaluate various treatment strategies for Gram-negative bloodstream infections (GN BSIs). Each domain addresses critical questions in the management of GN BSIs, aiming to refine treatment strategies, enhance patient outcomes, and reduce antimicrobial resistance.
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.
BALANCE+ is an adaptive platform trial evaluating multiple treatment options in patients admitted to the hospital due to Gram negative bloodstream infections (BSIs). It focuses on both cross-cutting and subgroup-specific questions, using an open-label, pragmatic design embedded in routine care.
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.
297 studies on the registry are indexed under Bacteremia; 51 are open to participants now.
This study's planned enrollment of 2,500 is above the median of 156 across 156 interventional studies indexed under Bacteremia.
Browse Bacteremia studies →Sunnybrook Health Sciences Centre is the lead sponsor of 584 studies on the registry; 135 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 2 (33%) have results posted.
Counted across the registry records on this site, refreshed daily.
The criteria were revised on the registry on Nov 9, 2026. See what changed
PLATFORM INCLUSION CRITERIA
Platform Inclusion Criteria:
Platform Exclusion Criteria:
DOMAIN SPECIFIC INCLUSION AND EXCLUSION CRITERIA
De-escalation versus no de-escalation domain
Inclusion Criteria
- included in BALANCE+ platform
Exclusion Criteria
no de-escalation option due to any or all of:
Beta-lactam versus non-beta-lactam oral/enteral treatment domain
Inclusion Criteria
Exclusion Criteria
no non-beta-lactam options due to any or all of:
no beta-lactam options due to any or all of:
Central vascular catheter replacement domain
Inclusion Criteria
Exclusion Criteria
ongoing septic shock with definite/probable line source o concomitant S. aureus bacteremia
Low-risk AmpC domain
Inclusion Criteria
Exclusion Criteria
- severe allergy to beta-lactams (e.g., type 4 reaction or DRESS)
Follow up blood culture domain
Inclusion Criteria
- included in BALANCE+ platform
Exclusion Criteria
4 day versus 7-day antibiotic duration
Inclusion Criteria • improving clinical trajectory, based on meeting all of these criteria by the 4th calendar day of adequate antibiotics:
o temperature 35.0ºC-37.9ºC
o not on vasopressors
o FiO2 ≤ 50%
Exclusion Criteria
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Other: De-escalation VS No De-escalation
Other: Oral beta-lactams VS non beta-lactams
Other: Central vascular catheter retention VS Central vascular catheter replacement
Other: Cephalosporin VS Carbapenem for low risk AmpC organisms
Enrollment to the domain has been completed.
Other: Routine follow-up blood culture VS No routine follow-up blood culture
Other: 4-day versus 7- day antibiotic duration
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).
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 replacement: the catheter will be changed by the treating team as soon as possible and within a maximum of 3 calendar days from blood culture finalization (removal must happen within that time; replacement can occur after that time point) Central vascular catheter retention: the catheter will not be changed and will be retained until it is non functional or no longer needed.
Cephalosporin (ceftriaxone) at standard doses Carbapenem (Meropenem or Ertapenem) at standard doses
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
The shorter duration arm will receive 4 days of adequate antibiotics. The longer duration arm will receive 7 days of adequate antibiotics.
Desirability of Outcome Ranking (DOOR) Ordinal Scale which incorporates death, reinfection, readmission, and for some domains incorporates a tie-breaker of new antimicrobial resistance (AMR).
The primary outcome for each domain will use a Desirability of Outcome Ranking (DOOR) ordinal scale in which patients are categorized into the following mutually exclusive categories, ranked from best to worst status: 1. Alive with no reinfection or readmission. 2. Alive with reinfection OR readmission. 3. Alive with reinfection AND readmission. 4. Dead For the 4 antibiotic-related domains (the de-escalation versus no de-escalation domain, the beta-lactam versus non-beta-lactam domain, the low risk AmpC domain, and the 4 versus 7 day duration domain) there will be an additional tie-breaker within ordinal levels 1, 2 and 3 based on whether there was new detection of antimicrobial resistance (AMR).
Time frame: 90 days
90-day mortality
Time frame: 90 days
90-day re-infection
Time frame: 90 days
90-day all cause readmission
Time frame: 90 days
90-day AMR colonization/infection
Time frame: 90 days
90-day Clostridioides difficile infection (CDI)
Time frame: 90 days
30-day mortality
Time frame: 30 days
60-day mortality
Time frame: 60 days
Additional Secondary Outcomes for Follow up blood culture domain
* total duration of antibiotic therapy * hospital length of stay
Time frame: 90 days
Additional Secondary Outcomes for De-escalation versus no de-escalation Domain
* change in total microbiome diversity between the day of randomization and discharge (or day 30 if earlier) * net change in resistome AMR burden between the day of randomization and discharge (or day 30 if earlier).
Time frame: 90 days
Additional Secondary Outcomes for Beta-lactam versus non-beta-lactam domain
* antibiotic-related allergic reaction * antibiotic-related adverse event
Time frame: 90 days
Additional Secondary Outcomes for Central vascular catheter replacement versus retention domain
* pneumothorax or thoracotomy tube insertion related to vascular catheter * clinically important bleeding * line associated thrombus * persistent bacteremia \>5d from initial index culture * secondary bloodstream infection with new bacterial or fungal organism
Time frame: 90 days
Additional Secondary Outcomes for Low-risk AmpC domain
* isolation of ESBL producing organism or third generation cephalosporin resistant Gram negative organism * isolation of a carbapenem-resistant organism
Time frame: 90 days
Additional domain-specific secondary outcomes in 4-day versus 7-day antibiotic duration
* antibiotic-related allergic reaction * antibiotic-related (non-allergic) adverse event (grade 4+ or 3+ with treatment change) * microbiome/resistome sub-study * change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 30 * change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 7 * net change in resistome AMR burden between the day of randomization and day 30 * change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 7
Time frame: 90 days
Started Apr 2024 (actual). Primary completion is estimated for Apr 2027, 36 months after the start.
Of 34 non-industry interventional studies with no phase under Bacteremia, half reached primary completion within 34 months of starting (the median), counting those still running; a quarter within 13 and three quarters within 64. This study's planned 36 months is close to that.
Counting every sponsor, half of 35 studies reached it within 34 months; a quarter within 13 and three quarters within 64.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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