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A Platform Trial for Gram Negative Bloodstream Infections

Not Applicable
Recruiting
Conditions
Gram-negative Bacteremia
Interventions
Other: Routine follow-up blood culture VS No routine follow-up blood culture
Other: Central vascular catheter retention VS Central vascular catheter replacement
Other: De-escalation VS No De-escalation
Other: Cephalosporin VS Carbapenem for low risk AmpC organisms
Other: Oral beta-lactams VS non beta-lactams
Registration Number
NCT06537609
Lead Sponsor
Sunnybrook Health Sciences Centre
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.

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
2500
Inclusion Criteria
  • admitted to a participating hospital
  • positive blood culture with Gram negative (GN) bacterium

Platform

Read More
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
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Routine follow-up blood culture VS No routine follow-up blood cultureRoutine follow-up blood culture VS No routine follow-up blood culture-
Central vascular catheter retention VS Central vascular catheter replacementCentral vascular catheter retention VS Central vascular catheter replacement-
De-escalation VS No De-escalationDe-escalation VS No De-escalation-
Cephalosporin VS Carbapenem for low risk AmpC organismsCephalosporin VS Carbapenem for low risk AmpC organisms-
Oral beta-lactams VS Oral Non-beta-lactamsOral beta-lactams VS non beta-lactams-
Primary Outcome Measures
NameTimeMethod
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 Outcome Measures
NameTimeMethod
90-day Clostridioides difficile infection (CDI)90 days
60-day mortality60 days
Additional Secondary Outcomes for Individual Domains90 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

90-day all cause readmission90 days
90-day AMR colonization/infection90 days
90-day mortality90 days
30-day mortality30 days
90-day re-infection90 days

Trial Locations

Locations (9)

Michael Garron Hospital

🇨🇦

Toronto, Ontario, Canada

Mount Sinai Hospital

🇨🇦

Toronto, Ontario, Canada

Sunnybrook Health Sciences Centre

🇨🇦

Toronto, Ontario, Canada

Université de Sherbrooke

🇨🇦

Sherbrooke, Quebec, Canada

Eastern Regional Health Authority

🇨🇦

Saint John's, Newfoundland and Labrador, Canada

University Health Network

🇨🇦

Toronto, Ontario, Canada

Foothills Hospital

🇨🇦

Calgary, Alberta, Canada

Niagara Health System

🇨🇦

St. Catharines, Ontario, Canada

The Ottawa Hospital

🇨🇦

Ottawa, Ontario, Canada

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