Clinical trial NCT06537609: A Platform Trial for Gram Negative Bloodstream Infections
Official title: BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Gram-negative Bacteremia
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2024-08-05
Enrollment: 2500
Sex: ALL
Minimum age (years): 0
Maximum age (years): 130
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: 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).
timeFrame: 90 days
Secondary outcomes:
measure: 90-day mortality
timeFrame: 90 days
measure: 90-day re-infection
timeFrame: 90 days
measure: 90-day all cause readmission
timeFrame: 90 days
measure: 90-day AMR colonization/infection
timeFrame: 90 days
measure: 90-day Clostridioides difficile infection (CDI)
timeFrame: 90 days
measure: 30-day mortality
timeFrame: 30 days
measure: 60-day mortality
timeFrame: 60 days
measure: Additional Secondary Outcomes for Individual Domains
timeFrame: 90 days
Other outcomes:
Locations:
city: Redcliffe
country: Australia
facility: Redcliffe Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Medical Center
state: Victoria
city: Murdoch
country: Australia
facility: St John of God
state: Western Australia
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Calgary
country: Canada
facility: Rockyview General Hospital
state: Alberta
city: Calgary
country: Canada
facility: South Health Campus
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Surrey
country: Canada
facility: Surrey Memorial Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Saint John's
country: Canada
facility: Eastern Regional Health Authority
state: Newfoundland and Labrador
city: North York
country: Canada
facility: North York General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montreal
country: Canada
facility: Montreal General Hospital- McGill
state: Quebec
city: Montreal
country: Canada
facility: Royal Victoria Hospital- McGill
state: Quebec
city: Sherbrooke
country: Canada
facility: Université de Sherbrooke
state: Quebec
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
state: Tel Aviv
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Nick Daneman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre
name: Rob Fowler, MD
role: PRINCIPAL_INVESTIGATOR
References: