Gram-negative Bacteremia
Conditions
Brief summary
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.
Detailed description
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.
Interventions
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 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 (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
Sponsors
Sunnybrook Health Sciences Centre
Canadian Institutes of Health Research (CIHR)
Clínica Universidad de La Sabana
Universidad de La Sabana, Colombia
Aotearoa Clinical Trials
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
PLATFORM INCLUSION CRITERIA Platform Inclusion Criteria: * admitted to a participating hospital * positive blood culture with Gram negative (GN) bacterium Platform
Exclusion criteria
* patient's goals of care are for palliation with no active treatment * moribund patient, not expected to survive \> 72 hours * previously enrolled in the platform trial * not eligible for any domain at the time of screening DOMAIN SPECIFIC INCLUSION AND
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | 90 days | 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 3 antibiotic-related domains (the de-escalation versus no de-escalation domain, the beta-lactam versus non-beta-lactam domain, and the low risk AmpC 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 90-day mortality | 90 days | — |
| 90-day re-infection | 90 days | — |
| 90-day all cause readmission | 90 days | — |
| 90-day AMR colonization/infection | 90 days | — |
| 90-day Clostridioides difficile infection (CDI) | 90 days | — |
| 30-day mortality | 30 days | — |
| 60-day mortality | 60 days | — |
| Additional Secondary Outcomes for Individual Domains | 90 days | (i) De-escalation versus no de-escalation * 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). (ii) Beta-lactam versus non-beta-lactam * antibiotic-related allergic reaction * antibiotic-related adverse event (iii) Central vascular catheter replacement versus retention * 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 (iv) Low-risk AmpC * isolation of ESBL producing organism or third generation cephalosporin resistant Gram negative organism * isolation of a carbapenem-resistant organism (v) Follow up blood culture domain * total duration of antibiotic therapy * hospital length of stay |
Countries
Australia, Canada, Colombia, Israel, New Zealand
Contacts
CONTACTNick Daneman, MD
CONTACTMithun Mohan George
PRINCIPAL_INVESTIGATORNick Daneman, MD
Sunnybrook Health Sciences Centre
PRINCIPAL_INVESTIGATORRob Fowler, MD
Sunnybrook Health Sciences Centre
Outcome results
None listed