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革兰氏阴性血流感染的平台试验 (BALANCE+)

2026年11月5日 更新者：Dr. Nick Daneman、Sunnybrook Health Sciences Centre

BALANCE+：革兰氏阴性血流感染的平台试验

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.

研究概览

地位

招聘中

条件

干预/治疗

详细说明

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.

研究类型

介入性

注册 (估计的)

2500

阶段

  • 不适用

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

研究联系人备份

学习地点

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

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

1秒 至 130年 (孩子、成人、年长者)

接受健康志愿者

不

有资格学习的性别

全部

描述

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

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：随机化
  • 介入模型：并行分配
  • 屏蔽：无（打开标签）

武器和干预

参与者组/臂
干预/治疗
有源比较器：降级 VS 不降级
其他：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).
有源比较器：口服 β-内酰胺 VS 口服非 β-内酰胺
其他：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.
有源比较器：中心血管导管保留 VS 中心血管导管置换
其他：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.
有源比较器：低风险 AmpC 生物体的头孢菌素 VS 碳青霉烯
其他：Cephalosporin VS Carbapenem for low risk AmpC organisms

Cephalosporin (ceftriaxone) at standard doses

Carbapenem (Meropenem or Ertapenem) at standard doses
有源比较器：Routine follow-up blood culture VS No routine follow-up blood culture

Enrollment to the domain has been completed.
其他：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
有源比较器：4-day versus 7-day antibiotic duration
其他：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.

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
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).
大体时间：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

次要结果测量

结果测量
措施说明
大体时间
30天死亡率
大体时间：30天
30天
90天死亡率
大体时间：90天
90天
60天死亡率
大体时间：60天
60天
90 天全因再入院
大体时间：90天
90天
90 天 AMR 定植/感染
大体时间：90天
90天
90 天艰难梭菌感染 (CDI)
大体时间：90天
90天
90天再次感染
大体时间：90天
90天
Additional Secondary Outcomes for Follow up blood culture domain
大体时间：90 days
  • total duration of antibiotic therapy
  • hospital length of stay
90 days
Additional Secondary Outcomes for De-escalation versus no de-escalation Domain
大体时间：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
大体时间：90 days
  • antibiotic-related allergic reaction
  • antibiotic-related adverse event
90 days
Additional Secondary Outcomes for Central vascular catheter replacement versus retention domain
大体时间：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
大体时间：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
大体时间：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

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

Sunnybrook Health Sciences Centre

合作者

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

调查人员

  • 首席研究员：Nick Daneman, MD、Sunnybrook Health Sciences Centre
  • 首席研究员：Rob Fowler, MD、Sunnybrook Health Sciences Centre

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (实际的)

2024年4月24日

初级完成 (估计的)

2027年4月1日

研究完成 (估计的)

2028年4月1日

研究注册日期

首次提交

2024年7月25日

首先提交符合 QC 标准的

2024年7月31日

首次发布 (实际的)

2024年8月5日

研究记录更新

最后更新发布 (实际的)

2026年11月9日

上次提交的符合 QC 标准的更新

2026年11月5日

最后验证

2026年10月1日

更多信息

与本研究相关的术语

其他研究编号

  • 4369-1

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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