A Platform Trial for Gram Negative Bloodstream Infections

Sunnybrook Health Sciences Centre

Status: Enrolling

Conditions: Gram-negative Bacteremia

Treatments: Other: Routine follow-up blood culture VS No routine follow-up blood culture; Other: De-escalation VS No De-escalation; Other: Cephalosporin VS Carbapenem for low risk AmpC organisms; Other: Central vascular catheter retention VS Central vascular catheter replacement; Other: Oral beta-lactams VS non beta-lactams

Study type: Interventional

Funder types: Other

Identifiers

NCT06537609

4369-1

Details and patient eligibility

About

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.

Full 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.

Enrollment: 2,500 estimated patients

Sex: All

Ages: Under 130 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 EXCLUSION CRITERIA

1. De-escalation versus no de-escalation domain

   Inclusion Criteria

   - included in BALANCE+ platform

   Exclusion Criteria

   • 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

   Inclusion Criteria

   • included in BALANCE+ platform
   • initially treated with intravenous antibiotics, but clinical team transitioning patient to oral/enteral antibiotic within 7 days of starting treatment

   Exclusion Criteria

   • 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

   Inclusion Criteria

   • 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)

   Exclusion Criteria

   • 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

   Inclusion Criteria

   • 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

   Exclusion Criteria

   • 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

Inclusion Criteria

- included in BALANCE+ platform

Exclusion Criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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2,500 participants in 5 patient groups

De-escalation VS No De-escalation

Active Comparator group

Treatment:

Other: De-escalation VS No De-escalation

Oral beta-lactams VS Oral Non-beta-lactams

Active Comparator group

Treatment:

Other: Oral beta-lactams VS non beta-lactams

Central vascular catheter retention VS Central vascular catheter replacement

Active Comparator group

Treatment:

Other: Central vascular catheter retention VS Central vascular catheter replacement

Cephalosporin VS Carbapenem for low risk AmpC organisms

Active Comparator group

Treatment:

Other: Cephalosporin VS Carbapenem for low risk AmpC organisms

Routine follow-up blood culture VS No routine follow-up blood culture

Active Comparator group

Treatment:

Other: Routine follow-up blood culture VS No routine follow-up blood culture