A Platform Trial for Gram Negative Bloodstream Infections (BALANCE+)

February 6, 2026 updated by: Dr. Nick Daneman, Sunnybrook Health Sciences Centre

BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

2500

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
      • Kogarah, New South Wales, Australia, 2217
        • Recruiting
        • St George Hospital
        • Principal Investigator:
          • Richard Sullivan
        • Contact:
        • Sub-Investigator:
          • Pam Konecny
        • Contact:
          • Rachael Roberts, Research Coordinator
      • New Lambton, New South Wales, Australia
        • Recruiting
        • John Hunter Hospital
        • Contact:
        • Contact:
          • Phone Number: +61 2 4921 3000
        • Principal Investigator:
          • Joshua Davis
    • Queensland
      • Herston, Queensland, Australia, 4006
        • Recruiting
        • Royal Brisbane and Women's Hospital
        • Contact:
        • Principal Investigator:
          • Patrick Harris, Infectious Disease Physician
      • Redcliffe, Queensland, Australia
        • Recruiting
        • Redcliffe Hospital
        • Principal Investigator:
          • Kevin O'Callaghan
        • Contact:
      • Sunshine Coast, Queensland, Australia
        • Recruiting
        • Sunshine Coast University Hospital
        • Contact:
        • Principal Investigator:
          • Gururaj Nagaraj
    • Victoria
      • Clayton, Victoria, Australia
        • Recruiting
        • Monash Medical Center
        • Principal Investigator:
          • Ben Rogers
        • Contact:
    • Western Australia
      • Murdoch, Western Australia, Australia
        • Recruiting
        • Fiona Stanley Hospital
        • Contact:
        • Principal Investigator:
          • Edward Raby
      • Murdoch, Western Australia, Australia
        • Recruiting
        • St John of God
        • Contact:
        • Principal Investigator:
          • Adrian Regli
  • Canada
    • Alberta
      • Calgary, Alberta, Canada
      • Calgary, Alberta, Canada
        • Recruiting
        • Peter Lougheed Centre
        • Principal Investigator:
          • Ranjani Somayaji
        • Contact:
      • Calgary, Alberta, Canada
        • Recruiting
        • South Health Campus
        • Principal Investigator:
          • Ranjani Somayaji
        • Contact:
      • Calgary, Alberta, Canada
        • Recruiting
        • Foothills Hospital
        • Contact:
          • Ranjani Somayaji, MD
      • Edmonton, Alberta, Canada
        • Recruiting
        • University of Alberta
        • Contact:
        • Principal Investigator:
          • Wendy Sligl
    • British Columbia
      • Surrey, British Columbia, Canada
        • Recruiting
        • Surrey Memorial Hospital
        • Principal Investigator:
          • Kevin Afra
        • Contact:
      • Vancouver, British Columbia, Canada
        • Recruiting
        • Vancouver General Hospital
        • Principal Investigator:
          • Jennifer Grant
        • Contact:
    • Manitoba
      • Winnipeg, Manitoba, Canada
        • Recruiting
        • Health Sciences Centre
        • Contact:
        • Principal Investigator:
          • Sylvain Lother
      • Winnipeg, Manitoba, Canada
        • Recruiting
        • St. Boniface Hospital
        • Principal Investigator:
          • Terry Wuerz
        • Contact:
      • Winnipeg, Manitoba, Canada
        • Recruiting
        • Grace Hospital
        • Contact:
        • Principal Investigator:
          • Gloria Vazquez-Grande
    • New Brunswick
      • Fredericton, New Brunswick, Canada
        • Recruiting
        • Dr. Everett Chalmers Regional Hospital
        • Contact:
        • Principal Investigator:
          • Rosa Rossana
    • Newfoundland and Labrador
      • St. John's, Newfoundland and Labrador, Canada
        • Recruiting
        • Eastern Regional Health Authority
        • Contact:
          • Peter Daley, MD
    • Ontario
      • Mississauga, Ontario, Canada
        • Not yet recruiting
        • Trillium Health Partners - Mississauga Hospital
        • Contact:
        • Contact:
          • Mobina Khurram
        • Principal Investigator:
          • Christopher Graham
      • North York, Ontario, Canada
        • Recruiting
        • North York General Hospital
        • Contact:
        • Principal Investigator:
          • Pavani Das
      • North York, Ontario, Canada
        • Recruiting
        • Humber River Health system
        • Contact:
        • Principal Investigator:
          • Ian Brasg
      • Ottawa, Ontario, Canada
        • Recruiting
        • The Ottawa Hospital
        • Contact:
          • Derek McFadden, MD
      • St. Catharines, Ontario, Canada
        • Recruiting
        • Niagara Health System
        • Contact:
          • Aidan Findlater, MD
      • Toronto, Ontario, Canada
        • Recruiting
        • Mount Sinai Hospital
        • Contact:
          • Michael Fralick, PhD
      • Toronto, Ontario, Canada, M4N3M5
        • Recruiting
        • Sunnybrook Health Sciences Centre
        • Contact:
        • Contact:
        • Principal Investigator:
          • Rob A Fowler, MD
        • Principal Investigator:
          • Nick Daneman, MD
      • Toronto, Ontario, Canada
        • Recruiting
        • University Health Network
        • Contact:
          • Bryan Coburn, MD
      • Toronto, Ontario, Canada
        • Recruiting
        • St. Joseph's Health Centre
        • Contact:
        • Principal Investigator:
          • Kevin Schwartz
      • Toronto, Ontario, Canada
        • Recruiting
        • Michael Garron Hospital
        • Contact:
          • Christopher Kandel, MD
    • Quebec
      • Laval, Quebec, Canada
        • Recruiting
        • CHU de Québec - Université Laval
        • Contact:
        • Principal Investigator:
          • Francois Lauzier
        • Sub-Investigator:
          • Julie Bestman-Smith
      • Laval, Quebec, Canada
        • Recruiting
        • Hôpital de la Cité de la Santé
        • Contact:
        • Principal Investigator:
          • Marco Bergevin
        • Sub-Investigator:
          • Stéphanie Castonguay
        • Sub-Investigator:
          • Olivier Haeck
        • Sub-Investigator:
          • Esther Simoneau
        • Sub-Investigator:
          • Marios Roussos
        • Sub-Investigator:
          • Natalie Rivest
        • Sub-Investigator:
          • Tuyen Nguyen
      • Montreal, Quebec, Canada
        • Recruiting
        • Montreal General Hospital- McGill
        • Contact:
        • Principal Investigator:
          • Emily McDonald
        • Principal Investigator:
          • Todd C Lee
      • Montreal, Quebec, Canada
        • Recruiting
        • Royal Victoria Hospital- McGill
        • Contact:
        • Principal Investigator:
          • Emily McDonald
        • Principal Investigator:
          • Todd C Lee
      • Sherbrooke, Quebec, Canada
        • Recruiting
        • Université de Sherbrooke
        • Contact:
          • Francois Lamontagne, MD
      • Trois-Rivières, Quebec, Canada, G8Z 3R9
        • Recruiting
        • Centre hospitalier affilié universitaire régional (CHAUR)
        • Principal Investigator:
          • Jean-francois Naud
        • Contact:
  • Colombia
    • Cundinamarca
      • Chía, Cundinamarca, Colombia
        • Recruiting
        • Universidad de La Sabana
        • Contact:
        • Principal Investigator:
          • Luis Felipe Reyes Velasco
  • Israel
    • Tel Aviv
      • Ramat Gan, Tel Aviv, Israel
        • Recruiting
        • Sheba Medical Center
        • Principal Investigator:
          • Dafna Yahav
        • Contact:
  • New Zealand
    • Auckland
      • Auckland, Auckland, New Zealand, 2025
        • Recruiting
        • Middlemore Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Susan Morpeth, Clinical Microbiologist
        • Sub-Investigator:
          • Michael Trent Herdman, Specialist Registrar

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: De-escalation VS No De-escalation
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).
Active Comparator: Oral beta-lactams VS Oral Non-beta-lactams
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.
Active Comparator: Central vascular catheter retention VS Central vascular catheter replacement
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.
Active Comparator: Cephalosporin VS Carbapenem for low risk AmpC organisms
Other: Cephalosporin VS Carbapenem for low risk AmpC organisms

Cephalosporin (ceftriaxone) at standard doses

Carbapenem (Meropenem or Ertapenem) at standard doses
Active Comparator: Routine follow-up blood culture VS No routine follow-up blood culture
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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

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).
90 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
30-day mortality
Time Frame: 30 days
30 days
90-day mortality
Time Frame: 90 days
90 days
60-day mortality
Time Frame: 60 days
60 days
90-day all cause readmission
Time Frame: 90 days
90 days
90-day AMR colonization/infection
Time Frame: 90 days
90 days
90-day Clostridioides difficile infection (CDI)
Time Frame: 90 days
90 days
90-day re-infection
Time Frame: 90 days
90 days
Additional Secondary Outcomes for Individual Domains
Time Frame: 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
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

Canadian Institutes of Health Research (CIHR)
Clínica Universidad de La Sabana
Aotearoa Clinical Trials
Universidad de La Sabana, Colombia

Investigators

  • Principal Investigator: Nick Daneman, MD, Sunnybrook Health Sciences Centre
  • Principal Investigator: Rob Fowler, MD, Sunnybrook Health Sciences Centre

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 24, 2024

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

April 1, 2028

Study Registration Dates

First Submitted

July 25, 2024

First Submitted That Met QC Criteria

July 31, 2024

First Posted (Actual)

August 5, 2024

Study Record Updates

Last Update Posted (Actual)

February 10, 2026

Last Update Submitted That Met QC Criteria

February 6, 2026

Last Verified

August 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4369-1

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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