A Platform Trial for Gram Negative Bloodstream Infections

Official title

BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

Overview

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

• Other De-escalation VS No De-escalation
  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).
• Other Oral beta-lactams VS non beta-lactams
  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.
• Other Central vascular catheter retention VS Central vascular catheter replacement
  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.
• Other Cephalosporin VS Carbapenem for low risk AmpC organisms
  Cephalosporin (ceftriaxone) at standard doses Carbapenem (Meropenem or Ertapenem) at standard doses
• Other Routine follow-up blood culture VS No routine follow-up blood culture
  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

Primary outcome measures

• 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). [Time frame: 90 days]

Secondary outcome measures (8)

• 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 Individual Domains [Time frame: 90 days]

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

• 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
• 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
• 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)
• 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
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 28 centers

• Foothills Hospital — Calgary
• Peter Lougheed Centre — Calgary
• Rockyview General Hospital — Calgary
• South Health Campus — Calgary
• University of Alberta — Edmonton
• Surrey Memorial Hospital — Surrey
• Vancouver General Hospital — Vancouver
• Grace Hospital — Winnipeg
• … and 20 more centers

Australia · 8 centers

• St George Hospital — Kogarah
• John Hunter Hospital — New Lambton
• Royal Brisbane and Women's Hospital — Herston
• Redcliffe Hospital — Redcliffe
• Sunshine Coast University Hospital — Sunshine Coast
• Monash Medical Center — Clayton
• Fiona Stanley Hospital — Murdoch
• St John of God — Murdoch

Colombia · 1 center

• Universidad de La Sabana — Chía

Israel · 1 center

• Sheba Medical Center — Ramat Gan

New Zealand · 1 center

• Middlemore Hospital — Auckland

Identifiers

NCT: NCT06537609 · 4369-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗