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Un essai de plateforme pour les infections sanguines à Gram négatif (BALANCE+)

5 novembre 2026 mis à jour par: Dr. Nick Daneman, Sunnybrook Health Sciences Centre

BALANCE+ : un essai de plateforme pour les infections sanguines à Gram négatif

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.

Aperçu de l'étude

Statut

Recrutement

Les conditions

Intervention / Traitement

Description détaillée

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.

Type d'étude

Interventionnel

Inscription (Estimé)

2500

Phase

  • N'est pas applicable

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Coordonnées de l'étude

Sauvegarde des contacts de l'étude

Lieux d'étude

  • Australie
    • New South Wales
      • Kogarah, New South Wales, Australie, 2217
        • Recrutement
        • St George Hospital
        • Chercheur principal:
          • Richard Sullivan
        • Contact:
        • Sous-enquêteur:
          • Pam Konecny
        • Contact:
          • Rachael Roberts, Research Coordinator
      • New Lambton, New South Wales, Australie
        • Recrutement
        • John Hunter Hospital
        • Contact:
        • Contact:
          • Numéro de téléphone: +61 2 4921 3000
        • Chercheur principal:
          • Joshua Davis
    • Queensland
      • Herston, Queensland, Australie, 4006
        • Recrutement
        • Royal Brisbane and Women's Hospital
        • Contact:
        • Chercheur principal:
          • Patrick Harris, Infectious Disease Physician
      • Redcliffe, Queensland, Australie
        • Recrutement
        • Redcliffe Hospital
        • Chercheur principal:
          • Kevin O'Callaghan
        • Contact:
      • Sunshine Coast, Queensland, Australie
        • Recrutement
        • Sunshine Coast University Hospital
        • Contact:
        • Chercheur principal:
          • Gururaj Nagaraj
    • Victoria
      • Clayton, Victoria, Australie
        • Recrutement
        • Monash Medical Center
        • Chercheur principal:
          • Ben Rogers
        • Contact:
    • Western Australia
      • Murdoch, Western Australia, Australie
        • Recrutement
        • Fiona Stanley Hospital
        • Contact:
        • Chercheur principal:
          • Edward Raby
      • Murdoch, Western Australia, Australie
        • Recrutement
        • St John of God
        • Contact:
        • Chercheur principal:
          • Adrian Regli
  • Canada
    • Alberta
      • Calgary, Alberta, Canada
      • Calgary, Alberta, Canada
        • Recrutement
        • Peter Lougheed Centre
        • Chercheur principal:
          • Ranjani Somayaji
        • Contact:
      • Calgary, Alberta, Canada
        • Recrutement
        • South Health Campus
        • Chercheur principal:
          • Ranjani Somayaji
        • Contact:
      • Calgary, Alberta, Canada
        • Recrutement
        • Foothills Hospital
        • Contact:
          • Ranjani Somayaji, MD
      • Edmonton, Alberta, Canada
        • Recrutement
        • University of Alberta
        • Contact:
        • Chercheur principal:
          • Wendy Sligl
    • British Columbia
      • Surrey, British Columbia, Canada
        • Recrutement
        • Surrey Memorial Hospital
        • Chercheur principal:
          • Kevin Afra
        • Contact:
      • Vancouver, British Columbia, Canada
        • Recrutement
        • Vancouver General Hospital
        • Chercheur principal:
          • Jennifer Grant
        • Contact:
    • Manitoba
      • Winnipeg, Manitoba, Canada
        • Recrutement
        • Health Sciences Centre
        • Contact:
        • Chercheur principal:
          • Sylvain Lother
      • Winnipeg, Manitoba, Canada
        • Recrutement
        • St. Boniface Hospital
        • Chercheur principal:
          • Terry Wuerz
        • Contact:
      • Winnipeg, Manitoba, Canada
        • Recrutement
        • Grace Hospital
        • Contact:
        • Chercheur principal:
          • Gloria Vazquez-Grande
    • New Brunswick
      • Fredericton, New Brunswick, Canada
        • Recrutement
        • Dr. Everett Chalmers Regional Hospital
        • Contact:
        • Chercheur principal:
          • Rosa Rossana
    • Newfoundland and Labrador
      • St. John's, Newfoundland and Labrador, Canada
        • Recrutement
        • Eastern Regional Health Authority
        • Contact:
          • Peter Daley, MD
    • Ontario
      • Mississauga, Ontario, Canada
        • Recrutement
        • Trillium Health Partners - Mississauga Hospital
        • Contact:
        • Contact:
          • Mobina Khurram
        • Chercheur principal:
          • Christopher Graham
      • North York, Ontario, Canada
        • Recrutement
        • Humber River Health system
        • Contact:
          • Ian Brasg
          • Numéro de téléphone: (416) 242-1000
          • E-mail: ibrasg@hrh.ca
        • Chercheur principal:
          • Ian Brasg
      • North York, Ontario, Canada
        • Recrutement
        • North York General Hospital
        • Contact:
        • Chercheur principal:
          • Pavani Das
      • Ottawa, Ontario, Canada
        • Recrutement
        • The Ottawa Hospital
        • Contact:
          • Derek McFadden, MD
      • St. Catharines, Ontario, Canada
        • Recrutement
        • Niagara Health System
        • Contact:
          • Aidan Findlater, MD
      • Toronto, Ontario, Canada
        • Recrutement
        • University Health Network
        • Contact:
          • Bryan Coburn, MD
      • Toronto, Ontario, Canada, M4N3M5
        • Recrutement
        • Sunnybrook Health Sciences Centre
        • Contact:
        • Contact:
        • Chercheur principal:
          • Rob A Fowler, MD
        • Chercheur principal:
          • Nick Daneman, MD
      • Toronto, Ontario, Canada
        • Recrutement
        • Michael Garron Hospital
        • Contact:
          • Christopher Kandel, MD
      • Toronto, Ontario, Canada
        • Recrutement
        • Mount Sinai Hospital
        • Contact:
          • Michael Fralick, PhD
      • Toronto, Ontario, Canada
        • Recrutement
        • St. Joseph's Health Centre
        • Contact:
        • Chercheur principal:
          • Kevin Schwartz
    • Quebec
      • Laval, Quebec, Canada
        • Recrutement
        • Hôpital de la Cité de la Santé
        • Contact:
        • Chercheur principal:
          • Marco Bergevin
        • Sous-enquêteur:
          • Stéphanie Castonguay
        • Sous-enquêteur:
          • Olivier Haeck
        • Sous-enquêteur:
          • Esther Simoneau
        • Sous-enquêteur:
          • Marios Roussos
        • Sous-enquêteur:
          • Natalie Rivest
        • Sous-enquêteur:
          • Tuyen Nguyen
      • Laval, Quebec, Canada
        • Recrutement
        • CHU de Québec - Université Laval
        • Contact:
        • Chercheur principal:
          • Francois Lauzier
        • Sous-enquêteur:
          • Julie Bestman-Smith
      • Montreal, Quebec, Canada
        • Recrutement
        • Montreal General Hospital- McGill
        • Contact:
        • Chercheur principal:
          • Todd C Lee
        • Chercheur principal:
          • Emily Mcdonald
      • Montreal, Quebec, Canada
        • Recrutement
        • Royal Victoria Hospital- McGill
        • Contact:
        • Chercheur principal:
          • Emily McDonald
        • Chercheur principal:
          • Todd C Lee
      • Sherbrooke, Quebec, Canada
        • Recrutement
        • Université de Sherbrooke
        • Contact:
          • François Lamontagne, MD
      • Trois-Rivières, Quebec, Canada, G8Z 3R9
        • Recrutement
        • Centre hospitalier affilié universitaire régional (CHAUR)
        • Contact:
        • Chercheur principal:
          • Jean-François Naud
  • Colombie
    • Cundinamarca
      • Chía, Cundinamarca, Colombie
        • Recrutement
        • Universidad de La Sabana
        • Contact:
        • Chercheur principal:
          • Luis Felipe Reyes Velasco
  • Israël
    • Tel Aviv
      • Ramat Gan, Tel Aviv, Israël
        • Recrutement
        • Sheba Medical Center
        • Chercheur principal:
          • Dafna Yahav
        • Contact:
  • Nouvelle-Zélande
    • Auckland
      • Auckland, Auckland, Nouvelle-Zélande, 2025
        • Recrutement
        • Middlemore Hospital
        • Contact:
        • Contact:
        • Chercheur principal:
          • Susan Morpeth, Clinical Microbiologist
        • Sous-enquêteur:
          • Michael Trent Herdman, Specialist Registrar
      • Takapuna, Auckland, Nouvelle-Zélande, 0622
    • Wellington Region
      • Newtown, Wellington Region, Nouvelle-Zélande, 6021
        • Recrutement
        • Wellington Hospital
        • Contact:
        • Chercheur principal:
          • Maxim Bloomfield
        • Sous-enquêteur:
          • Paul Young

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

1 seconde à 130 ans (Enfant, Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La 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 o 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 o concomitant S. aureus bacteremia o concomitant Candidemia o clinical suspicion for infective endocarditis

  6. 4 day versus 7-day antibiotic duration

    Inclusion Criteria • improving clinical trajectory, based on meeting all of these criteria by the 4th calendar day of adequate antibiotics:

    o temperature 35.0ºC-37.9ºC

    o not on vasopressors

    o FiO2 ≤ 50%

    Exclusion Criteria

    • Has not undergone successful source control (if required) before completing 4th calendar day of adequate antibiotics

    • Neutropenia (<0.5 × 10⁹/L)

    • solid organ or bone marrow transplantation
    • suspected or documented deep-seated infection requiring prolonged antibiotics

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Comparateur actif: Désescalade VS Pas de désescalade
Autre: 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).
Comparateur actif: Bêta-lactamines orales VS Non-bêta-lactamines orales
Autre: 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.
Comparateur actif: Rétention du cathéter vasculaire central VS Remplacement du cathéter vasculaire central
Autre: 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 3 calendar days from blood culture finalization (removal must happen within that time; replacement can occur after that time point)

Central vascular catheter retention: the catheter will not be changed and will be retained until it is non functional or no longer needed.
Comparateur actif: Céphalosporine VS Carbapénem pour les organismes AmpC à faible risque
Autre: Cephalosporin VS Carbapenem for low risk AmpC organisms

Cephalosporin (ceftriaxone) at standard doses

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

Enrollment to the domain has been completed.
Autre: 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
Comparateur actif: 4-day versus 7-day antibiotic duration
Autre: 4-day versus 7- day antibiotic duration

The shorter duration arm will receive 4 days of adequate antibiotics. The longer duration arm will receive 7 days of adequate antibiotics.

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
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).
Délai: 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 4 antibiotic-related domains (the de-escalation versus no de-escalation domain, the beta-lactam versus non-beta-lactam domain, the low risk AmpC domain, and the 4 versus 7 day duration 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

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Mortalité à 30 jours
Délai: 30 jours
30 jours
Mortalité à 90 jours
Délai: 90 jours
90 jours
Mortalité à 60 jours
Délai: 60 jours
60 jours
Réadmission toutes causes dans 90 jours
Délai: 90 jours
90 jours
Colonisation/infection par la RAM pendant 90 jours
Délai: 90 jours
90 jours
Infection à Clostridioides difficile (ICD) de 90 jours
Délai: 90 jours
90 jours
Réinfection de 90 jours
Délai: 90 jours
90 jours
Additional Secondary Outcomes for Follow up blood culture domain
Délai: 90 days
  • total duration of antibiotic therapy
  • hospital length of stay
90 days
Additional Secondary Outcomes for De-escalation versus no de-escalation Domain
Délai: 90 days
  • 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).
90 days
Additional Secondary Outcomes for Beta-lactam versus non-beta-lactam domain
Délai: 90 days
  • antibiotic-related allergic reaction
  • antibiotic-related adverse event
90 days
Additional Secondary Outcomes for Central vascular catheter replacement versus retention domain
Délai: 90 days
  • 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
90 days
Additional Secondary Outcomes for Low-risk AmpC domain
Délai: 90 days
  • isolation of ESBL producing organism or third generation cephalosporin resistant Gram negative organism
  • isolation of a carbapenem-resistant organism
90 days
Additional domain-specific secondary outcomes in 4-day versus 7-day antibiotic duration
Délai: 90 days

  • antibiotic-related allergic reaction

  • antibiotic-related (non-allergic) adverse event (grade 4+ or 3+ with treatment change)

  • microbiome/resistome sub-study

    • change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 30
    • change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 7
    • net change in resistome AMR burden between the day of randomization and day 30
    • change in total microbiome diversity (Shannon diversity index) between the day of randomization and day 7
90 days

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Sunnybrook Health Sciences Centre

Collaborateurs

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

Les enquêteurs

  • Chercheur principal: Nick Daneman, MD, Sunnybrook Health Sciences Centre
  • Chercheur principal: Rob Fowler, MD, Sunnybrook Health Sciences Centre

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

24 avril 2024

Achèvement primaire (Estimé)

1 avril 2027

Achèvement de l'étude (Estimé)

1 avril 2028

Dates d'inscription aux études

Première soumission

25 juillet 2024

Première soumission répondant aux critères de contrôle qualité

31 juillet 2024

Première publication (Réel)

5 août 2024

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

9 novembre 2026

Dernière mise à jour soumise répondant aux critères de contrôle qualité

5 novembre 2026

Dernière vérification

1 octobre 2026

Plus d'information

Termes liés à cette étude

Autres numéros d'identification d'étude

  • 4369-1

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Non

Étudie un produit d'appareil réglementé par la FDA américaine

Non

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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